U.S. patent application number 10/824738 was filed with the patent office on 2004-10-14 for sodium channel modulators.
Invention is credited to Chinn, Jason P., Choi, Seok-Ki, Fatheree, Paul R., Marquess, Daniel, Turner, S. Derek.
Application Number | 20040204460 10/824738 |
Document ID | / |
Family ID | 22861810 |
Filed Date | 2004-10-14 |
United States Patent
Application |
20040204460 |
Kind Code |
A1 |
Chinn, Jason P. ; et
al. |
October 14, 2004 |
Sodium channel modulators
Abstract
The invention provides sodium channel modulating compounds of
formula I: 1 wherein X, Y, Q, R.sup.1, w, and R.sup.2 have any of
the values defined in the specification, and salts thereof, which
are useful for treating diseases or conditions associated with
sodium channel activity, such as neuropathic pain. The invention
also provides pharmaceutical compositions comprising a compound of
formula (I) or a salt thereof, as well as therapeutic methods
comprising administering such a compound or salt to a mammal (e.g.
a human).
Inventors: |
Chinn, Jason P.; (Petaluma,
CA) ; Choi, Seok-Ki; (Palo Alto, CA) ;
Fatheree, Paul R.; (San Francisco, CA) ; Marquess,
Daniel; (Half Moon Bay, CA) ; Turner, S. Derek;
(Pacifica, CA) |
Correspondence
Address: |
THERAVANCE, INC.
901 GATEWAY BOULEVARD
SOUTH SAN FRANCISCO
CA
94080
US
|
Family ID: |
22861810 |
Appl. No.: |
10/824738 |
Filed: |
April 15, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10824738 |
Apr 15, 2004 |
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09943420 |
Aug 30, 2001 |
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6756400 |
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60229572 |
Aug 31, 2000 |
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Current U.S.
Class: |
514/357 ;
514/408; 514/561; 546/334; 548/577; 564/347 |
Current CPC
Class: |
C07D 211/22 20130101;
C07D 207/08 20130101; C07D 207/16 20130101; C07D 211/46 20130101;
C07D 453/02 20130101; C07C 217/20 20130101; A61P 25/02 20180101;
C07D 207/12 20130101; C07D 295/088 20130101 |
Class at
Publication: |
514/357 ;
514/408; 514/561; 546/334; 548/577; 564/347 |
International
Class: |
A61K 031/44; A61K
031/40; A61K 031/137 |
Claims
1-39. (canceled)
40. A compound selected from the group consisting of: (a) formula
X: 157(b) formula XII: 158(c) formula XVI: 159wherein in formulae
X, XII, and XVI: Q is methylene, 1,2-ethylene, 3,4-hexylene,
dimethylmethylene, oxy, --NH--, OCH.sub.2CH.sub.2O --, or a group
--C(R.sup.5)(R.sup.6)-- wherein R.sup.5 and R.sup.6 together with
the carbon to which they are attached from a cyclohexylene ring;
each X is independently oxy (--O--) or --NR.sup.m--; each R.sup.1
is independently C.sub.1-10alkyl or halo; each R.sup.2 is
independently a C.sub.2-10alkylene; wherein alkylene is optionally
substituted with 1 to 4 substituents independently selected from
R.sup.b; each Y is independently NR.sup.nR.sup.p; wherein for
R.sup.2, each alkyl is optionally substituted with R.sup.x, or with
1, 2, 3, or 4 substituents independently selected from R.sup.b;
each w is independently 0, 1, or 2; and (d) formula VIII:
160wherein Q' is methylene; each X is independently oxy (--O--) or
--NR.sup.m--; each R.sup.1a is C.sub.1-10alkyl or halo; each R2 is
independently a C.sub.2-10alkylene alkylene; wherein alkylene is
optionally substituted with 1 to 4 substituents independently
selected from R.sup.b; each Y is independently NR.sup.nR.sup.p;
wherein for R.sup.2, each alkyl is optionally substituted with
R.sup.x, or with 1, 2, 3, or 4 substituents independently selected
from R.sup.b; each w.sup.1 is independently 1 or 2; each R.sup.a is
independently --OR.sup.d, --NO.sub.2, halo, --S(O).sub.mR.sup.d,
--SR.sup.d, --S(O).sub.2OR.sup.d, --S(O).sub.mNR.sup.dR.sup.e,
--NR.sup.dR.sup.e, --O(CR.sup.fR.sup.g).sub.- nNR.sup.dR.sup.e,
--C(O)R.sup.d, --CO.sub.2R.sup.d,
--CO.sub.2(CR.sup.fR.sup.g).sub.nCONR.sup.dR.sup.e, --OC(O)R.sup.d,
--CN, --C(O)NR.sup.dR.sup.e, NR.sup.dC(O)R.sup.e,
--OC(O)NR.sup.dR.sup.e, --NR.sup.dC(O)OR.sup.e,
--NR.sup.dC(O)NR.sup.dR.sup.e, CR.sup.d(.dbd.N--OR.sup.e),
--CF.sub.3, or --OCF.sub.3; each R.sup.b is independently R.sup.a,
oxo or .dbd.N--OR.sup.e; each R.sup.d and R.sup.e is independently
hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or
heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl is optionally substituted
with 1 to 4 substituents independently selected from R.sup.h; or
R.sup.d and R.sup.e together with the atoms to which they are
attached form a heterocyclic ring having from 5 to 7 ring atoms,
wherein the heterocyclic ring optionally contains 1 or 2 additional
heteroatoms independently selected from oxygen, sulfur or nitrogen;
each R.sup.f and R.sup.g is independently hydrogen, alkyl, aryl,
heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl is optionally substituted
with 1 to 4 substituents independently selected from R.sup.h; or
R.sup.f and R.sup.g together with the carbon atom to which they are
attached form a ring having from 5 to 7 ring atoms, wherein the
ring optionally contains 1 or 2 heteroatoms independently selected
from oxygen, sulfur or nitrogen; each R.sup.h is independently
halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, aryl, (aryl)-C.sub.1-6alkyl,
heteroaryl, (heteroaryl)-C.sub.1-6alkyl, hydroxy, amino,
--NHC.sub.1-6alkyl, --N(C.sub.1-6alkyl).sub.2,
--OC(O)C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl, --C(O)OC.sub.1-6alkyl,
--NHC(O)C.sub.1-6alkyl, --C(O)NHC.sub.1-6alkyl, carboxy, nitro,
--CN, or --CF.sub.3; R.sup.m is hydrogen, alkyl, alkenyl, alkynyl,
aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl,
alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is
optionally substituted with 1 to 4 substituents independently
selected from R.sup.h; each R.sup.n and R.sup.p is independently
hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or
heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl is optionally substituted
with 1 to 4 substituents independently selected from R.sup.h; each
R.sup.x is independently aryl, heteroaryl, cycloalkyl or
heterocyclyl; wherein each aryl or heteroaryl is optionally
substituted with 1 to 4 substituents selected from the group
consisting of R.sup.c, and wherein each cycloalkyl and heterocyclyl
is optionally substituted with 1 to 4 substituents selected from
R.sup.b; m is 0, 1, or 2; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or
10; and or a pharmaceutically-acceptable salt thereof.
41. The compound of claim 40 wherein each R.sup.1 is independently
methyl or chloro.
42. The compound of claim 40 wherein each X is oxy.
43. The compound of claim 40 wherein each Y is independently amino,
diethylamino, or dimethylamino.
44. The compound of claim 40 wherein each R.sup.2 is independently
1,2-ethylene, 1,3-propylene, (2R)-2-(methyl)ethane-1,2-diyl,
(2S)-2-(methyl)ethane-1,2-diyl, 1-(methyl)butane-1,4-diyl,
1-(methyl)ethane-1,2-diyl, or 2,2-(dimethyl)propane-1,3-diyl.
45. The compound of claim 40 wherein Q is methylene.
46. The compound of claim 40 wherein w is 0.
47. The compound of claim 40 wherein w is 1.
48. The compound of claim 40 wherein w is 2.
49. The compound of claim 40 which is a compound of formula X.
50. The compound of claim 40 which is a compound of formula
XII.
51. The compound of claim 40 which is a compound of formula
XVI.
52. The compound of claim 40, which is selected from a compound of
formula X, formula XII, and formula XVI.
53. The compound of claim 40 which is a compound of formula
VIII.
54. The compound of claim 51, which is a compound of formula XXIX:
161
55. The compound of claim 53, which is a compound of formula XXX:
162
56. The compound of claim 53, which is a compound of formula XX:
163
57. The compound of claim 56, which is anyone of compounds 27, 28,
29, 30, 31, 36, and 37: 164or a pharmaceutically acceptable salt
thereof.
58. The compound of claim 54, which is any one of compounds 96, 97,
98, 129 and 131: 165or a pharmaceutically acceptable salt
thereof.
59. The compound of claim 40 which is any one of compounds 78, 86,
106, 173, and 140: 166
60. A compound which is any one of compounds 52, 53, 56, 61, 116,
117, 119, and 146: 167
61. A pharmaceutical composition comprising a compound selected
from the group consisting of: (a) formula X: 168(b) formula XII:
169(c) formula XVI: 170wherein in formulae X, XII, and XVI: Q is
methylene, 1,2-ethylene, 3,4-hexylene, dimethylmethylene, oxy,
--NH--, OCH.sub.2CH.sub.2O --, or a group --C(R.sup.5)(R.sup.6)--
wherein R.sup.5 and R.sup.6 together with the carbon to which they
are attached from a cyclohexylene ring; each X is independently oxy
(--O--) or --NR.sup.m--; each R.sup.1 is independently
C.sub.1-10alkyl or halo; each R.sup.2 is independently a
C.sub.2-10alkylene; wherein alkylene is optionally substituted with
1 to 4 substituents independently selected from R.sup.b; each Y is
independently NR.sup.nR.sup.p; wherein for R.sup.2, each alkyl is
optionally substituted with R.sup.x, or with 1, 2, 3, or 4
substituents independently selected from R.sup.b; each w is
independently 0, 1, or 2; and (d) formula VIII: 171wherein Q' is
methylene; 3,4-hexylene, oxy, --NH--, or OCH.sub.2CH.sub.2O --;
each X is independently oxy (--O--) or --NR.sup.m--; each R.sup.1
is independently C.sub.1-10alkyl or halo; each R.sup.2 is
independently a C.sub.2-10alkylene; wherein alkylene is optionally
substituted with 1 to 4 substituents independently selected from
R.sup.b; each Y is independently NR.sup.nR.sup.p; wherein for
R.sup.2, each alkyl is optionally substituted with R.sup.x, or with
1, 2, 3, or 4 substituents independently selected from R.sup.b;
each w.sup.1 is independently 1 or 2; each R.sup.a is independently
--OR.sup.d, --NO.sub.2, halo, --S(O).sub.mR.sup.d, --SR.sup.d,
--S(O).sub.2OR.sup.d, --S(O).sub.mNR.sup.dR.sup.e,
--NR.sup.dR.sup.e, --O(CR.sup.fR.sup.g).sub.- nNR.sup.dR.sup.e,
--C(O)R.sup.d, --CO.sub.2R.sup.d,
--CO.sub.2(CR.sup.fR.sup.gCONR.sup.dR.sup.e, --OC(O)R.sup.d, --CN,
--C(O)NR.sup.dR.sup.e, --NR.sup.dC(O)R.sup.e,
--OC(O)NR.sup.dR.sup.e, --NR.sup.dC(O)OR.sup.e,
--NR.sup.dC(O)NR.sup.dR.sup.e, --CR.sup.d(.dbd.N--OR.sup.e),
--CF.sub.3, or --OCF.sub.3; each R.sup.b is independently R.sup.a,
oxo or .dbd.N--OR.sup.e; each R.sup.d and R.sup.e is independently
hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or
heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl is optionally substituted
with 1 to 4 substituents independently selected from R.sup.h; or
R.sup.d and R.sup.e together with the atoms to which they are
attached form a heterocyclic ring having from 5 to 7 ring atoms,
wherein the heterocyclic ring optionally contains 1 or 2 additional
heteroatoms independently selected from oxygen, sulfur or nitrogen;
each R.sup.f and R.sup.g is independently hydrogen, alkyl, aryl,
heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl is optionally substituted
with 1 to 4 substituents independently selected from R.sup.h; or
R.sup.f and R.sup.g together with the carbon atom to which they are
attached form a ring having from 5 to 7 ring atoms, wherein the
ring optionally contains 1 or 2 heteroatoms independently selected
from oxygen, sulfur or nitrogen; each R.sup.h is independently
halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, aryl, (aryl)-C.sub.1-6alkyl,
heteroaryl, (heteroaryl)-C.sub.1-6alkyl, hydroxy, amino,
--NHC.sub.1-6alkyl, --N(C.sub.1-6alkyl).sub.2,
--OC(O)C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl, --C(O)OC.sub.1-6alkyl,
--NHC(O)C.sub.1-6alkyl, --C(O)NHC.sub.1-6alkyl, carboxy, nitro,
--CN, or --CF.sub.3; R.sup.m is hydrogen, alkyl, alkenyl, alkynyl,
aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl,
alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is
optionally substituted with 1 to 4 substituents independently
selected from R.sup.h; each R.sup.n and R.sup.p is independently
hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or
heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl is optionally substituted
with 1 to 4 substituents independently selected from R.sup.h; each
R.sup.x is independently aryl, heteroaryl, cycloalkyl or
heterocyclyl; wherein each aryl or heteroaryl is optionally
substituted with 1 to 4 substituents selected from the group
consisting of R.sup.c, and wherein each cycloalkyl and heterocyclyl
is optionally substituted with 1 to 4 substituents selected from
R.sup.b; m is 0, 1, or 2; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or
10; and or a pharmaceutically-acceptable salt thereof; and a
pharmaceutically acceptable carrier.
62. A pharmaceutical composition comprising a compound as described
in claim 40 and a pharmaceutically acceptable carrier.
63. A method of treating a disease or condition associated with
sodium channel activity in a mammal, comprising administering to
the mammal, a therapeutically effective amount of a pharmaceutical
composition comprising a compound as described in claim 40 and a
pharmaceutically acceptable carrier.
64. The method of claim 63 wherein the disease or condition is
neuropathic pain.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority from U.S. Provisional
Application No. 60/229,572, filed 31 Aug. 2000, the entire contents
of which is hereby incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The invention is directed to novel compounds that bind to
sodium channels and modulate their activity. The invention is also
directed to pharmaceutical compositions comprising such compounds,
methods of using such compounds to treat diseases associated with
the activity of sodium channels, and processes and intermediates
useful for preparing such compounds.
BACKGROUND
[0003] Voltage-gated ion channels play a critical role in the
electrical activity of neuronal and muscle cells. Large families of
voltage-gated ion channels (e.g. sodium channels) have been
identified. These ion channels have been the target of significant
pharmocologic study, due to their potential role in a variety of
pathological conditions.
[0004] For example, the activity of sodium channels has been
implicated in numerous pathological conditions, including
neuropathic pain. Neuropathic pain is a chronic condition
associated with diabetes, chronic inflammation, cancer and herpes
virus infection. An estimated 75 million people worldwide are
expected to suffer from neuropathic pain by the year 2010.
Unfortunately, current treatment options typically provide only
partial pain relief, and are limited by inconvenient dosing and by
side effects, such as somnolence, ataxia, edema, gastrointestinal
discomfort and respiratory depression.
[0005] Thus, despite the limited success that has been achieved
using sodium channel modulators to treat pain, there continues to
be a need for novel agents and methods that are useful for treating
neuropathic pain, as well as other conditions associated with the
activity of sodium channels. Particularly useful agents may be more
potent or cause fewer side effects than existing agents.
SUMARY OF THE INVENTION
[0006] The present invention provides novel compounds that bind to
sodium channels and modulate (e.g. block) their activity.
Accordingly, the invention provides a compound of the invention,
which is compound of formula I: 2
[0007] wherein:
[0008] Q is --O--, --S(O).sub.m--, --(CR.sup.5R.sup.6).sub.p--,
--O(CR.sup.5R.sup.6).sub.rO--, or --N(R.sup.k)--;
[0009] each R.sup.1 is independently alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl, heterocyclyl, or R.sup.a;
[0010] each R.sup.2 is independently a covalent bond or alkylene;
wherein alkylene is optionally substituted with 1 to 4 substituents
independently selected from R.sup.b;
[0011] each X is independently oxy (--O--) or --N(R.sup.m)--;
[0012] each Y is independently NR.sup.nR.sup.p or a heterocyclyl
containing at least one nitrogen atom, wherein each nitrogen of the
heterocyclyl is substituted with R.sup.3 or is linked to R.sup.2,
and wherein each heterocycle of Y is optionally substituted with 1,
2, 3, or 4 substituents independently selected from R.sup.4;
[0013] each R.sup.3 is independently hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, cycloalkyl, oxo, or heterocyclyl; and
each R.sup.4 is independently alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl, heterocyclyl, or R.sup.b; or R.sup.3 and
R.sup.4 are joined to form a C.sub.1-4 alkylene group, wherein the
alkylene group is optionally substituted with 1 to 4 substituents
independently selected from R.sup.b;
[0014] each R.sup.5 and R.sup.6 is independently hydrogen, alkyl,
alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; or
R.sup.5 and R.sup.6 together with the carbon atom to which they are
attached form a ring having from 5 to 7 ring atoms, wherein the
ring optionally contains 1 or 2 heteroatoms in the ring
independently selected from oxygen, sulfur or nitrogen;
[0015] wherein for R.sup.1-R.sup.6, each alkyl, alkenyl, and
alkynyl is optionally substituted with R.sup.x, or with 1, 2, 3, or
4 substituents independently selected from R.sup.b; for
R.sup.1-R.sup.6, each aryl and heteroaryl is optionally substituted
with 1 to 4 substituents independently selected from R.sup.c, and
for R.sup.1-R.sup.6, each cycloalkyl and heterocyclyl is optionally
substituted with 1 to 4 substituents independently selected from
R.sup.b and R.sup.c;
[0016] each R.sup.a is independently --OR.sup.d, --NO.sub.2, halo,
--S(O).sub.mR.sup.d, --SR.sup.d, --S(O).sub.2OR.sup.d,
--S(O).sub.mNR.sup.dR.sup.e, --NR.sup.dR.sup.e,
--O(CR.sup.fR.sup.g).sub.- nNR.sup.dR.sup.e, --C(O)R.sup.d,
--CO.sub.2R.sup.d,
--CO.sub.2(CR.sup.fR.sup.g).sub.nCONR.sup.dR.sup.e, --OC(O)R.sup.d,
--CN, --C(O)NR.sup.dR.sup.e, --NR.sup.dC(O)R.sup.e,
--OC(O)NR.sup.dR.sup.e, --NR.sup.dC(O)OR.sup.e,
--NR.sup.dC(O)NR.sup.dR.sup.e, --CR.sup.d(.dbd.N--OR.sup.e),
--CF.sub.3, or --OCF.sub.3;
[0017] each R.sup.b is independently R.sup.a, oxo or
.dbd.N--OR.sup.e;
[0018] each R.sup.c is independently R.sup.a, alkyl, alkenyl, or
alkynyl; wherein each alkyl, alkenyl and alkynyl is optionally
substituted with 1 to 4 substituents independently selected from
R.sup.b;
[0019] each R.sup.d and R.sup.e is independently hydrogen, alkyl,
alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl
and heterocyclyl is optionally substituted with 1 to 4 substituents
independently selected from R.sup.h; or R.sup.d and R.sup.e
together with the atoms to which they are attached form a
heterocyclic ring having from 5 to 7 ring atoms, wherein the
heterocyclic ring optionally contains 1 or 2 additional heteroatoms
independently selected from oxygen, sulfur or nitrogen;
[0020] each R.sup.f and R.sup.g is independently hydrogen, alkyl,
aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl,
aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally
substituted with 1 to 4 substituents independently selected from
R.sup.h; or R.sup.f and R.sup.g together with the carbon atom to
which they are attached form a ring having from 5 to 7 ring atoms,
wherein the ring optionally contains 1 or 2 heteroatoms
independently selected from oxygen, sulfur or nitrogen;
[0021] each R.sup.h is independently halo, C.sub.1-6alkyl,
C.sub.1-6alkoxy, aryl, (aryl)-C.sub.1-6alkyl, heteroaryl,
(heteroaryl)C.sub.1-6alkyl, hydroxy, amino, --NHC.sub.1-6alkyl,
--N(C.sub.1-6alkyl).sub.2, --OC(O)C.sub.1-6alkyl,
--C(O)C.sub.1-6alkyl, --C(O)OC.sub.1-6alkyl,
--NHC(O)C.sub.1-6alkyl, --C(O)NHC.sub.1-6 alkyl, carboxy, nitro,
--CN, or --CF.sub.3;
[0022] R.sup.k is hydrogen, alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl,
alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is
optionally substituted with 1 to 4 substituents independently
selected from R.sup.h;
[0023] R.sup.m is hydrogen, alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl,
alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is
optionally substituted with 1 to 4 substituents independently
selected from R.sup.h;
[0024] each R.sup.n and R.sup.p is independently hydrogen, alkyl,
alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl
and heterocyclyl is optionally substituted with 1 to 4 substituents
independently selected from R.sup.h; and
[0025] each R.sup.x is independnetly aryl, heteroaryl, cycloalkyl
or heterocyclyl; wherein each aryl or heteroaryl is optionally
substituted with 1 to 4 substituents selected from the group
consisting of R.sup.c, and wherein each cycloalkyl and heterocyclyl
is optionally substituted with 1 to 4 substituents selected from
R.sup.b;
[0026] m is 0, 1, or 2;
[0027] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
[0028] p is 1, 2, or 3;
[0029] r is 2, or 3; and
[0030] each w is independently 0, 1, 2, 3, or 4;
[0031] or a pharmaceutically-acceptable salt thereof;
[0032] provided that when any Y is NR.sup.nR.sup.p or a
nitrogen-linked heterocyclyl, then the R.sup.2 attached to that Y
is not a covalent bond or methylene.
[0033] The invention also provides a pharmaceutical composition
comprising a compound of the invention and pharmaceutically
acceptable carrier.
[0034] The invention also provides a method of treating a disease
or condition associated with sodium channel activity (e.g.
neuropathic pain) in a mammal, comprising administering to the
mammal, a therapeutically effective amount of a compound of the
invention. The invention also provides a method of treating a
disease or condition associated with sodium channel activity (e.g.
neuropathic pain) in a mammal, comprising administering to the
mammal, a therapeutically effective amount of a pharmaceutical
composition of the invention.
[0035] The invention also provides processes and intermediates
described herein, which are useful for preparing compounds of the
invention.
[0036] The invention also provides a compound of the invention as
described herein for use in medical therapy, as well as the use of
a compound of the invention in the manufacture of a formulation or
medicament for treating a disease or condition associated with
sodium channel activity (e.g. neuropathic pain) in a mammal.
[0037] Preferred compounds of the invention are the compounds of
formula I shown in Table I below.
1TABLE I Preferred Compounds of Formula I Compound Structure 1 3 8
4 9 5 10 6 11 7 12 8 13 9 14 10 15 11 16 12 17 13 18 14 19 15 20 16
21 17 22 18 23 19 24 20 25 21 26 22 27 23 28 24 29 25 30 26 31 27
32 28 33 29 34 30 35 31 36 32 37 33 38 34 39 35 40 36 41 37 42 38
43 39 44 40 45 41 46 42 47 43 48 44 49 45 50 46 51 47 52 48 53 49
54 50 55 51 56 52 57 53 58 54 59 55 60 56 61 57 62 58 63 59 64 60
65 61 66 62 67 63 68 64 69 65 70 66 71 67 72 68 73 69 74 70 75 71
76 72 77 73 78 74 79 75 80 76 81 77 82 78 83 79 84 80 85 81 86 82
87 83 88 84 89 85 90 86 91 87 92 88 93 89 94 90 95 91 96 92 97 93
98 94 99 95 100 96 101 97 102 98 103 99 104 100 105 101 106 102 107
103 108 104 109 105 110 106 111 107 112 108 113 109 114 110 115 111
116 112 117 113 118 114 119 115 120 116 121 117 122 118 123 119 124
120 125 121 126 122 127 123 128 124 129 125 130 126 131 127 132 128
133 129 134 130 135 131 136 132 137 133 138 134 139 135 140 136 141
137 142 138 143 139 144 140 145 141 146 142 147 143 148 144 149 145
150 146 151 147 152 148 153 149 154 150
DESCRIPTION OF THE FIGURES
[0038] FIGS. 1-3 illustrate compounds of formulae V-XXX that are
compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0039] When describing the compounds, compositions and methods of
the invention, the following terms have the following meanings,
unless otherwise indicated.
[0040] The term "alkyl" refers to a monovalent saturated
hydrocarbon group which may be linear or branched or combinations
thereof. Such alkyl groups preferably contain from 1 to 20 carbon
atoms; more preferably, from 1 to 10 carbon atoms; and still more
preferably, from 1 to 6 carbon atoms. Representative alkyl groups:
include, by way of example, methyl, ethyl, n-propyl, isopropyl,
n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,
n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
[0041] The term "alkenyl" refers to a monovalent unsaturated
hydrocarbon group containing at least one carbon-carbon double
bond, typically 1 or 2 carbon-carbon double bonds, and which may be
linear or branched or combinations thereof. Such alkenyl groups
preferably contain from 2 to 20 carbon atoms; more preferably from
2 to 10 carbon atoms; and still more preferably, from 2 to 6 carbon
atoms. Representative alkenyl groups include, by way of example,
vinyl, allyl, isopropenyl, but-2-enyl, n-pent-2-enyl, n-hex-2-enyl,
n-hept-2-enyl, n-oct-2-enyl, n-non-2-enyl, n-dec-4-enyl,
n-dec-2,4-dienyl and the like.
[0042] The term "alkynyl" refers to a monovalent unsaturated
hydrocarbon group containing at least one carbon-carbon triple
bond, typically 1 carbon-carbon triple bond, and which may be
linear or branched or combinations thereof. Such alkynyl groups
preferably contain from 2 to 20 carbon atoms; more preferably from
2 to 10 carbon atoms; and still more preferably, from 2 to 6 carbon
atoms. Representative alkynyl groups include, by way of example,
ethynyl, propargyl, but-2-ynyl and the like.
[0043] The term "alkoxy" refers to a group of the formula --OR,
where R is an alkyl group as defined herein. Representative alkoxy
groups include, by way of example, methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy,
n-pentoxy, n-hexoxy and the like.
[0044] The term "alkylene" refers to a divalent saturated
hydrocarbon group which may be linear or branched or combinations
thereof. Such alkylene groups preferably contain from 1 to 20
carbon atoms; more preferably, from 1 to 10 carbon atoms; and still
more preferably, from 1 to 6 carbon atoms. Representative alkylene
groups include, by way of example, methylene, ethylene, propylene
and the like.
[0045] The term "cycloalkyl" refers to a monovalent saturated
carbocyclic group which may be monocyclic or multicyclic. Each ring
of such cycloalkyl groups preferably contains from 3 to 10 carbon
atoms. This term also includes cycloalkyl groups fused to an aryl
or heteroaryl group in which the point of attachment is on the
non-aromatic (cycloalkyl) portion of the group. Representative
cycloalkyl groups include, by way of example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
1,2,3,4-tetrahydronaphth-2-yl, decahydronaphthyl, indan-1-yl,
adamantyl, norbornyl and the like.
[0046] The term "aryl" refers to a monovalent unsaturated aromatic
carbocyclic group which may be monocyclic or multicyclic (i.e.,
fused). Such aryl groups preferably contain from 6 to 20 carbon
atoms; more preferably, from 6 to 10 carbon atoms. This term also
includes aryl groups fused to a cycloalkyl or heterocyclyl group in
which the point of attachment is on the aromatic (aryl) portion of
the group. Representative aryl groups include, by way of example,
phenyl, napthyl, azulenyl, indan-5-yl,
1,2,3,4-tetrahydronaphth-6-yl, 2,3-dihydrobenzofuran-5-yl and the
like.
[0047] The term "heteroaryl" refers to a monovalent aromatic group
which contains at least one heteroatom, preferably 1 to 4
heteroatoms, selected from N, S and O within at least one aromatic
ring and which may be monocyclic or multicyclic (i.e., fused). Such
heteroaryl groups preferably contain from 5 to 20 atoms; more
preferably, from 5 to 10 atoms. This term also includes heteroaryl
groups fused to a cycloalkyl or heterocyclyl group in which the
point of attachment is on the aromatic (heteroaryl) portion of the
group. Representative heteroaryl groups include, by way of example,
pyrroyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl,
oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl,
tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl,
pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,
benzofuranyl, benzothiophenyl, quinolyl, indolyl, isoquinolyl and
the like.
[0048] The term "heterocyclyl" or "heterocyclic" refers to a
monovalent saturated or partially unsaturated cyclic non-aromatic
group which contains at least one heteroatom, preferably 1 to 4
heteroatoms, selected from N, S and O within at least one cyclic
ring and which maybe monocyclic or muliticyclic. Such heterocyclyl
groups preferably contain from 3 to 20 atoms; more preferably, from
3 to 10 atoms. The point of attachment of the heterocyclyl group
may be a carbon or nitrogen atom. This term also includes
heterocyclyl groups fused to an aryl or heteroaryl group in which
the point of attachment is on the non-aromatic (heterocyclyl)
portion of the group. Representative heterocyclyl groups include,
by way of example, pyrrolidinyl, piperidinyl, piperazinyl,
imidazolidinyl, morpholinyl, indolin-3-yl, 2-imidazolinyl,
1,2,3,4-tetrahydroisoquinolin-2-yl, quinuclidinyl and the like.
[0049] The term "halo" refers to a fluoro, chloro, bromo or
iodo.
[0050] The term "oxo" refers to a group of the formula .dbd.O.
[0051] The term "pharmaceutically-acceptable salt" refers to a salt
prepared from a base or acid which is acceptable for administration
to a patient, such as a mammal. Such salts can be derived from
pharmaceutically-acceptable inorganic or organic bases and from
pharmaceutically-acceptable inorganic or organic acids. Salts
derived from pharmaceutically-acceptable inorganic bases include
aluminum, ammonium, calcium, copper, ferric, ferrous, lithium,
magnesium, manganic, manganous, potassium, sodium, zinc and the
like. Particularly preferred are ammonium, calcium, magnesium,
potassium and sodium salts. Salts derived from
pharmaceutically-acceptable organic bases include salts of primary,
secondary and tertiary amines, including substituted amines, cyclic
amines, naturally-occuring amines and the like, such as arginine,
betaine, caffeine, choline, N,N'-dibenzylethylenediamine,
diethylaamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylenediamine, N-ethylmorpholine,
N-ethylpiperidine, glucamine, glucosanine, histidine, hydrabamine,
isopropylamine, lysine, methylglucamine, morpholine, piperazine,
piperadine, polyamine resins, procaine, purines, theobromine,
triethylamine, trimethylamine, tripropylamine, tromethamine and the
like. Salts derived from pharmaceutically-acceptable acids include
acetic, benzenesulfonic, benzoic, camphosulfonic, citric,
ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,
hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,
succinic, sulfuric, tartaric, p-toluenesulfonic and the like.
Particularly preferred are citric, hydrobromic, hydrochloric,
maleic, phosphoric, sulfuric and tartaric acids.
[0052] The term "therapeutically effective amount" refers to an
amount sufficient to effect treatment when administered to a
patient in need of treatment.
[0053] The term "treatment" as used herein refers to the treatment
of a disease or medical condition in a patient, such as a mammal
(particularly a human) which includes:
[0054] (a) preventing the disease or medical condition from
occurring, i.e., prophylactic treatment of a patient;
[0055] (b) ameliorating the disease or medical condition, i.e.,
eliminating or causing regression of the disease or medical
condition in a patient;
[0056] (c) suppressing the disease or medical condition, i.e.,
slowing or arresting the development of the disease or medical
condition in a patient; or
[0057] (d) alleviating the symptoms of the disease or medical
condition in a patient.
[0058] The phrase "disease or condition associated with sodium
channel activity" includes all disease states and/or conditions
that are acknowledged now, or that are found in the future, to be
associated with the activity of sodium channels. Such disease
states include, but are not limited to, pathophysiological
disorders, including hypertension, cardiac arrhythmogenesis,
insulin-dependent diabetes, non-insulin dependent diabetes
mellitus, diabetic neuropathy, seizures, tachycardia, ischemic
heart disease, cardiac failure, angina, myocardial infarction,
transplant rejection, autoimmune disease, sickle cell anemia,
muscular dystrophy, gastrointestinal disease, mental disorder,
sleep disorder, anxiety disorder, eating disorder, neurosis,
alcoholism, inflammation, cerebrovascular ischemia, CNS diseases,
epilepsy, Parkinson's disease, asthma, incontinence, urinary
dysfunction, micturition disorder, irritable bowel syndrome,
restenosis, subarachnoid hemorrhage, Alzheimers disease, drug
dependence/addiction, schizophrenia, Huntington's chorea,
tension-type headache, trigeminal neuralgia, cluster headache,
migraine (acute and prophylaxis), inflammatory pain, neuropathic
pain and depression.
[0059] "Pharmaceutically acceptable salt" means those salts which
retain the biological effectiveness and properties of the parent
compounds and which are not biologically or otherwise harmful as
the dosage administered. The compounds of this invention are
capable of forming both acid and base salts by virtue of the
presence of amino and carboxy groups respectively.
[0060] Pharmaceutically acceptable base addition salts may be
prepared from inorganic and organic bases. Salts derived from
inorganic bases include, but are not limited to, the sodium,
potassium, lithium, ammonium, calcium, and magnesium salts. Salts
derived from organic bases include, but are not limited to, salts
of primary, secondary and tertiary amines, substituted amines
including naturally-occurring substituted amines, and cyclic
amines, including isopropylamine, timethyl amine, diethylamine,
triethylamnine, tripropylamine, ethanolamine,
2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine,
caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,
glucosamine, N-alkylglucamines, theobrornine, purines, piperazine,
piperidine, and N-ethylpiperidine. It should also be understood
that other carboxylic acid derivatives would be useful in the
practice of this invention, for example carboxylic acid amides,
including carboxamides, lower alkyl carboxamides, di(lower alkyl)
carboxamides, and the like.
[0061] Pharmaceutically acceptable acid addition salts may be
prepared from inorganic and organic acids. Salts derived from
inorganic acids include hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid and the like. Salts
derived from organic acids include acetic acid, propionic acid,
glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid,
succinic acid, maleic acid, fumaric acid, tartaric acid, citric
acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid
and the like.
[0062] The compounds of the invention may contain one or more
chiral centers. Accordingly, the invention includes racemic
mixtures, diasteromers, enantiomers and mixture enriched in one or
more steroisomer. The scope of the invention as described and
claimed encompasses the racemic forms of the compounds as well as
the individual enantiomers and non-racemic mixtures thereof.
[0063] Specific and preferred values listed below for radicals,
substituents, and ranges, are for illustration only, they do not
exclude other defined values or other values within defined ranges
for the radicals and substituents
[0064] A specific value for each R.sup.1 is independently
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10 alkynyl, cycloalkyl,
or R.sup.a.
[0065] A specific value for each R.sup.1 is independently
C.sub.1-10alkyl or halo.
[0066] A more specific value for each R.sup.1 is independently
methyl, ethyl, propyl, chloro, bromo, fluoro, or isopropyl.
[0067] A more specific value for each R.sup.1 is independently
methyl, or chloro.
[0068] A specific value for each R.sup.2 is independently a
covalent bond or C.sub.1-10alkylene.
[0069] A more specific value for each R.sup.2 is independently a
covalent bond, methylene, 1,2-ethylene, 1,3-propylene,
(2R)-2-(methyl)ethane-1,2-d- iyl, (2S)2-(methyl)ethane-1,2-diyl,
1-(methyl)butane-1,4-diyl, 1-(methyl)ethane-1,2-diyl, or
2,2-(dimethyl)propane-1,3-diyl.
[0070] A specific value for each R.sup.2 is independently a
covalent bond, methylene, or ethylene.
[0071] A specific value for Q is --O--, --S(O).sub.m--, or
--(CR.sup.5R.sup.6).sub.p--.
[0072] A specific value for Q is --O--, --S(O).sub.m--, or
--N(R.sup.k)--.
[0073] A specific value for Q is --(CR.sup.5R.sup.6).sub.p--, or
--O(CR.sup.5R.sup.6).sub.rO--.
[0074] A specific value for Q is --O--, --S(O).sub.m--,
--(CR.sup.5R.sup.6).sub.p--, or --N(R.sup.k)--;
[0075] A more specific value for Q is methylene, 1,2-ethylene,
3,4-hexylene, dimethylmethylene, oxy, --NH--,
--OCH.sub.2CH.sub.2O--, or a group --C(R.sup.5)(R.sup.6)-- wherein
R.sup.5 and R.sup.6 together with the carbon to which they are
attached form a cyclohexylene ring.
[0076] A specific value for X is oxy.
[0077] A specific value for X is --NH--.
[0078] A specific value for each Y is independently
NR.sup.nR.sup.p.
[0079] A specific value for each Y is independently a heterocyclyl
containing at least one nitrogen atom, wherein each nitrogen of the
heterocyclyl is substituted with R.sup.3 or linked to R.sup.2, and
wherein each heterocycle of Y is optionally substituted with 1, 2,
3, or 4 substituents independently selected from R.sup.4.
[0080] A specific value for each Y is independently a heterocyclyl
containing at least one nitrogen atom, wherein each nitrogen of the
heterocyclyl is substituted with R.sup.3.
[0081] A specific value for each Y is independently a heterocyclyl
containing at least one nitrogen atom, wherein each nitrogen of the
heterocyclyl is linked to R.sup.2, and wherein each heterocycle of
Y is optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.4.
[0082] A specific value for each Y is independently a heterocyclyl
selected from pyrrolidinyl, piperidinyl, and morpholinyl, wherein
each heterocycle of Y is optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.4.
[0083] A specific value for each Y is independently a heterocyclyl
selected from pyrrolidino, piperidino, and morpholino, wherein each
heterocycle of Y is optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.4.
[0084] A more specific value for each Y is independently amino,
diethylamino, dimethylamino, 1-methyl-4-piperidinyl,
1-methyl-3-piperidinyl, 1-methyl-2-piperidinyl, 4-piperidinyl,
3-piperidinyl, 2-piperidinyl, 1-isopropyl-3-pyrrolidinyl,
morpholino, (2R,4R)-2-methoxycarbonyl-4-pyrrolidinyl,
1-methyl-3-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 3-pyrrolidinyl,
2-pyrrolidinyl, 1-pyrrolidinyl, (2S,4R)-2-methyl-4-pyrrolidinyl,
(2R,4R)-2-carboxy-4-pyrrolidinyl,
(2S,4S)-2-(N,N-dimethylamino)carbonyl-4-pyrrolidinyl,
(2R,4R)-2-hydroxymethyl-4-pyrrolidinyl, or
(2R,4R)-2-methoxymethyl-4-pyrr- olidinyl.
[0085] A specific value for each w is 0.
[0086] A specific value for each w is 1.
[0087] A specific value for each w is 2.
[0088] A specific value for each y is independently 1 or 2.
[0089] A specific value for each z is independently 0, 1, or 2.
[0090] A specific group of compounds of formula I are compounds
wherein each R.sub.2 is independently a covalent bond or methylene;
Q is SO.sub.2 or --CR.sup.5R.sup.6--; each w is independently 0, 1,
or 2; and each y is 1 or 2.
[0091] A preferred compound of formula I is a compound of formula
II: 151
[0092] wherein:
[0093] Q is --O--, --S(O).sub.m--, or --CR.sup.5R.sup.6--;
[0094] each R.sup.1 is independently alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl, heterocyclyl, or R.sup.a;
[0095] each R.sup.2 is independently a covalent bond or alkylene;
wherein alkylene is optionally substituted with 1 to 4 substituents
independently selected from R.sup.b;
[0096] each R.sup.3 is independently hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, cycloalkyl, oxo, or heterocyclyl; and
each R.sup.4 is independently alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl, heterocyclyl, or R.sup.b; or R.sup.3 and
R.sup.4 are joined to form a C.sub.1-4 alkylene group, wherein the
alkylene group is optionally substituted with 1 to 4 substituents
independently selected from R.sup.b;
[0097] each R.sup.5 and R.sup.6 is independently hydrogen, alkyl,
alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; or
R.sup.5 and R.sup.6 together with the carbon atom to which they are
attached form a ring having from 5 to 7 ring atoms, wherein the
ring optionally contains 1 or 2 heteroatoms in the ring
independently selected from oxygen, sulfur and nitrogen;
[0098] wherein for R.sup.1-R.sup.6, each alkyl, alkenyl, and
alkynyl is optionally substituted with R.sup.x, or with 1 to 4
substituents independently selected from R.sup.b; each aryl and
heteroaryl is optionally substituted with 1 to 4 substituents
independently selected from R.sup.c, and each cycloalkyl and
heterocyclyl is optionally substituted with 1 to 4 substituents
independently selected from R.sup.b and R.sup.c;
[0099] each R.sup.a is independently --OR.sup.d, --NO.sub.2, halo,
--S(O).sub.mR.sup.d, --SR.sup.d, --S(O).sub.2OR.sup.d,
--S(O).sub.mNR.sup.dR.sup.e, --NR.sup.dR.sup.e,
--O(CR.sup.fR.sup.g)NR.su- p.dR.sup.e, --C(O)R.sup.d,
--CO.sub.2R.sup.d, --CO.sub.2(CR.sup.fR.sup.g).-
sub.nCONR.sup.dR.sup.e, --OC(O)R.sup.d, --CN,
--C(O)NR.sup.dR.sup.e, --NR.sup.dC(O)R.sup.e,
--OC(O)NR.sup.dR.sup.e, --NR.sup.dC(O)OR.sup.e,
--NR.sup.dC(O)NR.sup.dR.sup.e, --CR.sup.d(.dbd.N--OR.sup.e),
--CF.sub.3, or --OCF.sub.3;
[0100] each R.sup.b is independently R.sup.a, oxo or
.dbd.N--OR.sup.e;
[0101] each R.sup.c is independently R.sup.a, alkyl, alkenyl, or
alkynyl; wherein each alkyl, alkenyl and alkynyl is optionally
substituted with 1 to 4 substituents independently selected from
R.sup.b;
[0102] each R.sup.d and R.sup.e is independently hydrogen, alkyl,
alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl
and heterocyclyl is optionally substituted with 1 to 4 substituents
independently selected from R.sup.h; or R.sup.d and R.sup.e
together with the atoms to which they are attached form a
heterocyclic ring having from 5 to 7 ring atoms, wherein the
heterocyclic ring optionally contains 1 or 2 additional heteroatoms
independently selected from oxygen, sulfur and nitrogen;
[0103] each R.sup.f and R.sup.g is independently hydrogen, alkyl,
aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl,
aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally
substituted with 1 to 4 substituents independently selected from
R.sup.h; or R.sup.f and R.sup.g together with the carbon atom to
which they are attached form a ring having from 5 to 7 ring atoms,
wherein the ring optionally contains 1 or 2 heteroatoms
independently selected from oxygen, sulfur and nitrogen;
[0104] each R.sup.h is independently halo, C.sub.1-6alkyl,
C.sub.1-6alkoxy, aryl, (aryl)-C.sub.1-6alkyl, heteroaryl,
(heteroaryl)-C.sub.1-6alkyl, hydroxy, amino, --NHC.sub.1-6alkyl,
--N(C.sub.1-6alkyl).sub.2, --OC(O)C.sub.1-6alkyl,
--C(O)C.sub.1-6alkyl, --C(O)OC.sub.1-6alkyl,
--NHC(O)C.sub.1-6alkyl, --C(O)NHC.sub.1-6alkyl, carboxy, nitro,
--CN, or --CF.sub.3; and
[0105] each R.sup.x is independently aryl, heteroaryl, cycloalkyl
or heterocyclyl; wherein each aryl or heteroaryl is optionally
substituted with 1 to 4 substituents selected from the group
consisting of R.sup.c, and wherein each cycloalkyl and heterocyclyl
is optionally substituted with 1 to 4 substituents selected from
R.sup.b;
[0106] m is 0, 1, or 2;
[0107] n is an integer from 1 to 10;
[0108] each w is independently 0, 1, 2, 3, or 4;
[0109] each y is independently 0, 1, 2, or 3; and
[0110] each z is independently 0, 1, 2, 3, or 4;
[0111] or a pharmaceutically-acceptable salt thereof.
[0112] Specifically, for a compound of formula II, each R.sup.1 can
independently be C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, cycloalkyl, or R.sup.a.
[0113] Specifically, for a compound of formula II, each R.sup.1 can
independently be C.sub.1-10alkyl or halo.
[0114] Specifically, for a compound of formula II, each R.sup.1 can
independently be methyl, ethyl, propyl, chloro, bromo, fluoro, or
isopropyl.
[0115] Specifically, for a compound of formula II, each R.sup.2 can
independently be a covalent bond or C.sub.1-10alkylene.
[0116] Specifically, for a compound of formula II, each R.sup.2 can
independently be a covalent bond, methylene, ethylene, propylene,
or isopropylene.
[0117] Specifically, for a compound of formula II, each R.sup.3 can
independently be hydrogen, C.sub.1-10alkyl, or oxo.
[0118] Specifically, for a compound of formula II, each R.sup.3 can
independently be hydrogen, methyl, ethyl, propyl, isopropyl,
benzyl, phenethyl, or pyridylmethyl.
[0119] Specifically, for a compound of formula II, each R.sup.3 can
independently be hydrogen, methyl, ethyl, propyl, or isopropyl.
[0120] Specifically, for a compound of formula II, each R.sup.4 can
independently be C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, or R.sup.b.
[0121] Specifically, for a compound of formula II, R.sup.3 and
R.sup.4 can be joined to form a C.sub.1-4 alkylene group, wherein
the alkylene group is optionally substituted with 1 to 4
substituents independently selected from R.sup.b.
[0122] Specifically, for a compound of formula II, Q can be
SO.sub.2 or --CR.sup.5R.sup.6--.
[0123] Specifically, for a compound of formula II, each each
R.sup.5 and R.sup.6 can independently be hydrogen, or
C.sub.1-10alkyl.
[0124] Specifically, for a compound of formula II, R.sup.5 and
R.sup.6 together with the carbon atom to which they are attached
can form a ring having from 5 to 7 ring atoms, wherein the ring
optionally contains 1 or 2 heteroatoms in the ring independently
selected from oxygen, sulfur and nitrogen.
[0125] Specifically, for a compound of formula II, each R.sup.1 and
R.sup.5 together with the carbon atom to which they are attached
can form a carbocyclic ring having from 5 to 7 atoms.
[0126] Specifically, for a compound of formula II, each w can be
0.
[0127] Specifically, for a compound of formula II, each each w can
be 1.
[0128] Specifically, for a compound of formula II, each w can be
2.
[0129] Specifically, for a compound of formula II, each y can
independently be 1 or 2.
[0130] Specifically, for a compound of formula II, each z can
independently be 0, 1, or 2.
[0131] A specific compound of formula II is a compound wherein
R.sub.2 is a covalent bond or methylene; Q is SO.sub.2 or
--CR.sup.5R.sup.6--; each w is independently 0, 1, or 2; and each y
is 1 or 2.
[0132] A specific compound of formula II is-a compound of formula
III: 152
[0133] wherein
[0134] Q is --O--, --S(O).sub.m--, or --CR.sup.5R.sup.6--;
[0135] each R.sup.7 is independently hydrogen, C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, cycloalkyl, or R.sup.a;
[0136] each R.sup.2 is independently a covalent bond or
C.sub.1-6alkylene; wherein alkylene is optionally substituted with
1 to 4 substituents independently selected from R.sup.b;.
[0137] each R.sup.3 is independently hydrogen, C.sub.1-10alkyl, or
oxo (forming an N-oxide);
[0138] each R.sup.5 and R.sup.6 is independently hydrogen or
C.sub.1-10alkyl; or R.sup.5 and R.sup.6 together with the carbon
atom to which they are attached form a ring having from 5 to 7 ring
atoms, wherein the ring optionally contains 1 or 2 heteroatoms in
the ring independently selected from oxygen, sulfur and
nitrogen;
[0139] wherein for R.sup.3, R.sup.5, R.sup.6, and R.sup.7, each
alkyl, alkenyl, and alkynyl is optionally substituted with R.sup.x,
or with 1 to 4 substituents independently selected from R.sup.b;
and each cycloalkyl is optionally substituted with 1 to 4
substituents independently selected from R.sup.b and R.sup.c;
[0140] each R.sup.a is independently --OR.sup.d, --NO.sub.2, halo,
--S(O).sub.mR.sup.d, --SR.sup.d, --S(O).sub.2OR.sup.d,
--S(O).sub.mNR.sup.dR.sup.e, --NR.sup.dR.sup.e,
--O(CR.sup.fR.sup.g).sub.- nNR.sup.dR.sup.e, --C(O)R.sup.d,
--CO.sub.2R.sup.d,
--CO.sub.2(CR.sup.fR.sup.g).sub.nCONR.sup.dR.sup.e, --OC(O)R.sup.d,
--CN, --C(O)NR.sup.dR.sup.e, --NR.sup.dC(O)R.sup.e,
--OC(O)NR.sup.dR.sup.e, --NR.sup.dC(O)OR.sup.e,
--NR.sup.dC(O)NR.sup.dR.sup.e, --CR.sup.d(.dbd.N--OR.sup.e),
--CF.sub.3, or --OCF.sub.3;
[0141] each R.sup.b is independently R.sup.a, oxo or
.dbd.N--OR;
[0142] each R.sup.c is independently R.sup.a, C.sub.1-10alkyl,
C.sub.2-10alkenyl, or C.sub.2-10alkynyl; wherein each alkyl,
alkenyl and alkynyl is optionally substituted with 1 to 4
substituents independently selected from R.sup.b;
[0143] each R.sup.d and R.sup.e is independently hydrogen,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10 alkynyl, aryl,
heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl,
alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is
optionally substituted with 1 to 4 substituents independently
selected from R.sup.h; or R.sup.d and R.sup.e together with the
atoms to which they are attached form a heterocyclic ring having
from 5 to 7 ring atoms, wherein the heterocyclic ring optionally
contains 1 or 2 additional heteroatoms independently selected from
oxygen, sulfur and nitrogen;
[0144] each R.sup.f and R.sup.g is independently hydrogen,
C.sub.1-10alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
wherein each alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl
is optionally substituted with 1 to 4 substituents independently
selected from R.sup.h; or R.sup.f and R.sup.g together with the
carbon atom to which they are attached form a ring having from 5 to
7 ring atoms, wherein the ring optionally contains 1 or 2
heteroatoms independently selected from oxygen, sulfur and
nitrogen;
[0145] each R.sup.h is independently halo, C.sub.1-6alkyl,
C.sub.1-6alkoxy, aryl, (aryl)-C.sub.1-6alkyl, heteroaryl,
(heteroaryl)-C.sub.1-6alkyl, hydroxy, amino, --NHC.sub.1-6alkyl,
--N(C.sub.1-6alkyl).sub.2, --OC(O)C.sub.1-6alkyl,
--C(O)C.sub.1-4alkyl, --C(O)OC.sub.1-6alkyl,
--NHC(O)C.sub.1-6alkyl, --C(O)NHC.sub.1-6alkyl, carboxy, nitro,
--CN, or --CF.sub.3; and
[0146] each R.sup.x is independently aryl, heteroaryl, cycloalkyl
or heterocyclyl; wherein each aryl or heteroaryl is optionally
substituted with 1 to 4 substituents selected from the group
consisting of R.sup.a, and wherein each cycloalkyl and heterocyclyl
is optionally substituted with 1 to 4 substituents selected from
R.sup.b; and
[0147] each y is independently 1, 2, or 3;
[0148] or a pharmaceutically-acceptable salt thereof
[0149] Specifically, each R.sup.7 can independently be hydrogen,
C.sub.1-10alkyl or halo.
[0150] Specifically, each R.sup.7 can independently be methyl,
ethyl, propyl, chloro, bromo, fluoro, or isopropyl.
[0151] A specific compound of formula I is a compound of any one of
formulae V-XXX, shown in FIGS. 1-3, wherein X, Y, Q, R.sup.1,
R.sup.2, and w have any of the values, specific values, or
preferred values defined herein.
[0152] For a compound of any one of formulae V-XXX, a specific
value for R.sup.1 is methyl, or chloro.
[0153] For a compound of any one of formulae V-XXX, a specific
value for Q is methylene, 1,2-ethylene, 3,4-hexylene,
dimethylmethylene, oxy, --NH--, --OCH.sub.2CH.sub.2O--, or a group
--C(R.sup.5)(R.sup.6)-- wherein R.sup.5 and R.sup.6 together with
the carbon to which they are attached form a cyclohexylene
ring.
[0154] For a compound of any one of formulae V-XXX, a specific
value for X is oxy or --NH--.
[0155] For a compound of any one of formulae V-XXX, a specific
value for R.sup.2 is a covalent bond, methylene, 1,2-ethylene,
1,3-propylene, (2R)2-(methyl)ethane-1,2-diyl,
(2S)-2-(methyl)ethane-1,2-diyl, 1-(methyl)butane- 1,4-diyl,
1-methyl)ethane-1,2-diyl, or 2,2-(dimethyl)propane-1,3-diyl.
[0156] For a compound of any one of formulae V-XXX, a specific
value for Y is amino, diethylamino, dimethylamino,
1-methyl-4-piperidinyl, 1-methyl-3-piperidinyl,
1-methyl-2-piperidinyl, 4-piperidinyl, 3-piperidinyl,
2-piperidinyl, 1-isopropyl-3-pyrrolidinyl, morpholino,
(2R,4R)-2-methoxycarbonyl-4-pyrrolidinyl, 1-methyl-3-pyrrolidinyl,
1-methyl-2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolidinyl,
1-pyrrolidinyl, (2S,4R)-2-methyl-4-pyrrolidinyl,
(2R,4R)-2-carboxy-4-pyrrolidinyl,
(2S,4S)-2-(N,N-dimethylamino)carbonyl-4-pyrrolidinyl,
(2R,4R)-2-hydroxymethyl-4-pyrrolidinyl, or
(2R,4R)-2-methoxymethyl-4-pyrr- olidinyl.
[0157] A preferred compound of the invention is a compound of any
one of formulae V-XXX, wherein each R.sup.1 is independently
methyl, or chloro; Q is methylene, 1,2-ethylene, 3,4-hexylene,
dimethylmethylene, oxy, --NH--, --OCH.sub.2CH.sub.2O--, or a group
--C(R.sup.5)(R.sup.6)-- wherein R.sup.5 and R.sup.6 together with
the carbon to which they are attached form a cyclohexylene ring;
each X is independently oxy or --NH--; each R.sup.2 is
independently a covalent bond, methylene, 1,2-ethylene,
1,3-propylene, (2R)-2-(methyl)ethane-1,2-diyl,
(2S)-2-(methyl)ethane-1,2-diyl, 1-(methyl)butane-1,4-diyl,
1-(methyl)ethane-1,2-diyl, or 2,2-(dimethyl)propane-1,3-diyl; and
each Y is independently amino, diethylamino, dimethylamino,
1-methyl-4-piperidinyl, 1-methyl-3-piperidinyl,
1-methyl-2-piperidinyl, 4-piperidinyl, 3-piperidinyl 2-piperidinyl,
1-isopropyl-3-pyrrolidinyl, morpholino,
(2R,4R)-2-methoxycarbonyl-4-pyrrolidinyl, 1-methyl-3-pyrrolidinyl,
1-methyl-2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolidinyl,
1-pyrrolidinyl, (2S,4R)-2-methyl-4-pyrrolidinyl,
(2R,4R)-2-carboxy-4-pyrrolidinyl,
(2S,4S-2-(N,N-dimethylamino)carbonyl-4-- pyrrolidinyl,
(2R,4R)-2-hydroxymethyl-4pyrrolidinyl, or
(2R,4R)-2-methoxymethyl-4-pyrrolidinyl.
[0158] Another preferred compound of formula I is a compound of
formula XX: 153
[0159] wherein Q is methylene, 1,2-ethylene, 3,4-hexylene,
dimethylmethylene, oxy, or a group --C(R.sup.5)(R.sup.6)-- wherein
R.sup.5 and R.sup.6 together with the carbon to which they are
attached form a cyclohexylene ring. Preferably, for a compound of
formula XX, each R.sup.1 is independently methyl or chloro.
[0160] Another preferred compound of formula I is a compound of
formula XXIX: 154
[0161] wherein Q is methylene. Preferably, for a compound of
formula XXIX, each R.sup.1 is independently chloro.
[0162] Another preferred compound of formula I is a compound of
formula XXX: 155
[0163] wherein Q is methylene. Preferably, for a compound of
formula XXX, each R.sup.1 is chloro.
[0164] General Synthetic Procedures
[0165] The compounds of the invention can be prepared using the
following general methods and procedures. It will be appreciated
that where typical or preferred process conditions (i.e., reaction
temperatures, times, mole ratios of reactants, solvents, pressures,
etc.) are given, other process conditions can also be used unless
otherwise stated. Optimum reaction conditions may vary with the
particular reactants or solvent used, but such conditions can be
determined by one skilled in the art by routine optimization
procedures.
[0166] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group, as well as suitable conditions for protection and
deprotection, are well known in the art. For example, numerous
protecting groups, and their introduction and removal, are
described in T. W. Greene and G. M. Wuts, Protecting Groups in
Organic Synthesis, Third Edition, Wiley, New York, 1999, and
references cited therein.
[0167] Processes for preparing compounds of formula I are provided
as further embodiments of the invention and are illustrated by the
following procedures in which the meanings of the generic radicals
are as given above unless otherwise qualified. For example, a
compound of formula I (wherein each X is oxy) an be prepared from
an intermediate diol of formula (I) by condensation with two
equivalents of the alcohol ROH, as illustrated in the following
scheme. 156
[0168] reagents and conditions suitable for preparing this
bis-ether of formula I from the diol of formula IV are well known
in the art. For example, the reaction can conveniently be carried
out under conditions similar to those described in the Examples
below.
[0169] Pharmaceutical Compositions
[0170] The invention also provides pharmaceutical compositions
comprising a compound of the invention. Accordingly, the compound,
preferably in the form of a pharmaceutically acceptable salt, can
be formulated for oral or parenteral administration for the
therapeutic or prophylactic treatment of diseases or conditions
associated with sodium channel activity.
[0171] By way of illustration, the compound can be admixed with
conventional pharmaceutical carriers and excipients and used in the
form of tablets, capsules, elixirs, suspensions, syrups, wafers,
and the like. Such pharmaceutical compositions will contain from
about 0.1 to about 90% by-weight of the active compound, and more
generally from about 10 to about 30%. The pharmaceutical
compositions may contain common carriers and excipients, such as
corn starch or gelatin, lactose, sucrose, microcrystalline
cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride,
and alginic acid. Disintegrators commonly used in the formulations
of this invention include croscarmellose, microcrystalline
cellulose, corn starch, sodium starch glycolate and alginic
acid.
[0172] A liquid composition will generally consist of a suspension
or solution of the compound or pharmaceutically acceptable salt in
a suitable liquid carrier(s), for example ethanol, glycerine,
sorbitol, non-aqueous solvent such as polyethylene glycol, oils or
water, optionally with a suspending agent, a solubilizing agent
(such as a cyclodextrin), preservative, surfactant, wetting agent,
flavoring or coloring agent. Alternatively, a liquid formulation
can be prepared from a reconstitutable powder.
[0173] For example a powder containing active compound, suspending
agent, sucrose and a sweetener can be reconstituted with water to
form a suspension; and a syrup can be prepared from a powder
containing active ingredient, sucrose and a sweetener.
[0174] A composition in the form of a tablet can be prepared using
any suitable pharmaceutical carrier(s) routinely used for preparing
solid compositions. Examples of such carriers include magnesium
stearate, starch, lactose, sucrose, microcrystalline cellulose and
binders, for example polyvinylpyrrolidone. The tablet can also be
provided with a color film coating, or color included as part of
the carrier(s). In addition, active compound can be formulated in a
controlled release dosage form as a tablet comprising a hydrophilic
or hydrophobic matrix.
[0175] A composition in the form of a capsule can be prepared using
routine encapsulation procedures, for example by incorporation of
active compound and excipients into a hard gelatin capsule.
Alternatively, a semi-solid matrix of active compound and high
molecular weight polyethylene glycol can be prepared and filled
into a hard gelatin capsule; or a solution of active compound in
polyethylene glycol or a suspension in edible oil, for example
liquid paraffin or fractionated coconut oil can be prepared and
filled into a soft gelatin capsule.
[0176] Tablet binders that can be included are acacia,
methylcellulose, sodium carboxymethylcellulose,
poly-vinylpyrrolidone (Povidone), hydroxypropyl methylcellulose,
sucrose, starch and ethylcellulose. Lubricants that can be used
include magnesium stearate or other metallic stearates, stearic
acid, silicone fluid, talc, waxes, oils and colloidal silica.
[0177] Flavoring agents such as peppermint, oil of wintergreen,
cherry flavoring or the like can also be used. Additionally, it may
be desirable to add a coloring agent to make the dosage form more
attractive in appearance or to help identify the product.
[0178] The compounds of the invention and their pharmaceutically
acceptable salts that are active when given parenterally can be
formulated for intramuscular, intrathecal, or intravenous
administration.
[0179] A typical composition for intra-muscular or intrathecal
administration will consist of a suspension or solution of active
ingredient in an oil, for example arachis oil or sesame oil. A
typical composition for intravenous or intrathecal administration
will consist of a sterile isotonic aqueous solution containing, for
example active ingredient and dextrose or sodium chloride, or a
mixture of dextrose and sodium chloride. Other examples are
lactated Ringer's injection, lactated Ringer's plus dextrose
injection, Normosol-M and dextrose, Isolyte E, acylated Ringer's
injection, and the like. Optionally, a co-solvent, for example,
polyethylene glycol; a chelating agent, for example,
ethylenediamine tetracetic acid; a solubilizing agent, for example,
a cyclodextrin; and an anti-oxidant, for example, sodium
metabisulphite, may be included in the formulation. Alternatively,
the solution can be freeze dried and then reconstituted with a
suitable solvent just prior to administration.
[0180] The compounds of the invention and their pharmaceutically
acceptable salts which are active on rectal administration can be
formulated as suppositories. A typical suppository formulation will
generally consist of active ingredient with a binding and/or
lubricating agent such as a gelatin or cocoa butter or other low
melting vegetable or synthetic wax or fat.
[0181] The compounds of this invention and their pharmaceutically
acceptable salts which are active on topical administration can be
formulated as transdermal compositions or transdermal delivery
devices ("patches"). Such compositions include, for example, a
backing, active compound reservoir, a control membrane, liner and
contact adhesive. Such transdermal patches may be used to provide
continuous or discontinuous infusion of the compounds of the
present invention in controlled amounts. The construction and use
of transdermal patches for the delivery of pharmaceutical agents is
well known in the art. See, e.g., U.S. Pat. No. 5,023,252, issued
Jun. 11, 1991. Such patches may be constructed for continuous,
pulsatile, or on demand delivery of pharmaceutical agents.
[0182] The active compound is effective over a wide dosage range
and is generally administered in a therapeutically effective
amount. It, will be understood, however, that the amount of the
compound actually administered will be determined by a physician,
in the light of the relevant circumstances, including the condition
to be treated, the chosen route of administration, the actual
compound administered and its relative activity, the age, weight,
and response of the individual patient, the severity of the
patient's symptoms, and the like.
[0183] Suitable doses are in the general range of from 0.01-100
mg/kg/day, preferably 0.1-50 mg/kg/day. For an average 70 kg human,
this would amount to 0.7 mg to 7 g per day, or preferably 7 mg to
3.5 g per day.
[0184] In general, an effective amount of a compound of this
invention is a dose between about 0.5 and about 100 mg/kg. A
preferred dose is from about 1 to about 60 mg/kg of active
compound. A typical daily dose for an adult human is from about 50
mg to about 5 g.
[0185] According to the invention, a compound can be administered
in a single daily dose or in multiple doses per day. The treatment
regimen may require administration over extended periods of time,
for example, for several days or for from one to six weeks.
[0186] Suitable formulations for use in the present invention can
be found in Remington's Pharmaceutical Sciences, Mace Publishing
Company, Philadelphia, Pa., 17th ed. (1985). The following
non-limiting examples illustrate representative pharmaceutical
compositions of the invention.
Formulation Example A
[0187] This example illustrates the preparation of a representative
pharmaceutical composition for oral administration of a compound of
this invention:
2 Ingredients Quantity per tablet, (mg) Active Compound 200
Lactose, spray-dried 148 Magnesium stearate 2
[0188] The above ingredients are mixed and introduced into a
hard-shell gelatin capsule.
Formulation Example B
[0189] This example illustrates the preparation of another
representative pharmaceutical composition for oral administration
of a compound of this invention:
3 Ingredients Quantity per tablet, (mg) Active Compound 400
Cornstarch 50 Lactose 145 Magnesium stearate 5
[0190] The above ingredients are mixed intimately and pressed into
single scored tablets.
Formulation Example C
[0191] This example illustrates the preparation of a representative
pharmaceutical composition for oral administration of a compound of
this invention.
[0192] An oral suspension is prepared having the following
composition.
4 Ingredients Active Compound 1.0 g Fumaric acid 0.5 g Sodium
chloride 2.0 g Methyl paraben 0.1 g Granulated sugar 25.5 g
Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g
flavoring 0.035 ml Colorings 0.5 mg Distilled water q.s. to 100
mL
Formulation Example D
[0193] This example illustrates the preparation of a representative
pharmaceutical composition containing a compound of this
invention.
[0194] An injectable preparation buffered to a pH of 4 is prepared
having the following composition:
5 Ingredients Active Compound 0.2 g Sodium Acetate Buffer Solution
(0.4 M) 2.0 mL HCl (1 N) q.s. to pH 4 Water (distilled, sterile)
q.s. to 20 mL
Formulation Example E
[0195] This example illustrates the preparation of a representative
pharmaceutical composition for injection of a compound of this
invention.
[0196] A reconstituted solution is prepared by adding 20 mL of
sterile water to 1 g of the compound of this invention. Before use,
the solution is then diluted with 200 mL of an intravenous fluid
that is compatible with the active compound. Such fluids are chosen
from 5% dextrose solution, 0.9% sodium chloride, or a mixture of 5%
dextrose and 0.9% sodium chloride. Other examples are lactated
Ringer's injection, lactated Ringer's plus 5% dextrose injection,
Normosol-M and 5% dextrose, Isolyte E, and acylated Ringer's
injection
Formulation Example F
[0197] This example illustrates the preparation of a representative
pharmaceutical composition containing a compound of this
invention.
[0198] An injectable preparation is prepared having the following
composition:
6 Ingredients Active Compound 0.1-5.0 g
Hydroxypropyl-.beta.-cyclodextrin 1-25 g 5% Aqueous Dextrose
Solution (sterile) q.s. to 100 mL
[0199] The above ingredients are blended and the pH is adjusted to
3.5.+-.0.5 using 0.5 N HCl or 0.5 N NaOH.
Formulation Example G
[0200] This example illustrates the preparation of a representative
pharmaceutical composition for topical application of a compound of
this invention.
7 Ingredients grams Active compound 0.2-10 Span 60 2 Tween 60 2
Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05
BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100
[0201] All of the above ingredients, except water, are combined and
heated to 60.degree. C. with stirring. A sufficient quantity of
water at 60.degree. C. is then added with vigorous stirring to
emulsify the ingredients, and water then added q.s. 100 g.
Formulation Example H
[0202] This example illustrates the preparation of a representative
pharmaceutical composition containing a compound of this
invention.
[0203] A suppository totaling 2.5 grams is prepared having the
following composition:
8 Ingredients Active Compound 500 mg Witepsol H-15* balance
(*triglycerides of saturated vegetable fatty acid; a product of
Riches-Nelson, Inc., New York, N.Y.)
[0204] Utility
[0205] The compounds of this invention, and their pharmaceutically
acceptable salts, exhibit biological activity and are useful for
medical treatment. The ability of a compound to block sodium
channel activity or to treat neuropathic pain can be demonstrated
using the tests described herein, or can be demonstrated using
tests that are known in the art.
[0206] The following synthetic and biological examples are offered
to illustrate the invention, and are not to be construed in any way
as limiting the scope of the invention.
EXAMPLES
[0207] In the examples below, the following abbreviations have the
following meanings. Any abbreviations not defined have their
generally accepted meaning. Unless otherwise stated, all
temperatures are in degrees Celsius.
[0208] BOC, Boc=tert-butoxycarbonyl
[0209] DCM=dichloromethane
[0210] DMSO=dimethyl sulfoxide
[0211] EtOAc=ethyl acetate
[0212] HATU=O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate
[0213] HOAT=1-hydroxy-7-azabenzotriazole
[0214] TFA=trifluoroacetic acid
[0215] THF=tetrahydrofuran
[0216] MeCN acetonitrile
[0217] MgSO.sub.4 anhydrous magnesium sulfate
[0218] General: Unless noted otherwise, reagents, starting material
(including amino alcohols, and bis-phenols) and solvents were
purchased from commercial suppliers (Aldrich, Fluka, Sigma, and
etc.), and used without further purification; reactions were run
under nitrogen atmosphere; reaction mixtures were monitored by thin
layer chromatography (silica TLC), analytical high performance
liquid chromatography (anal. HPLC), or mass spectrometry; reaction
mixtures were commonly purified by flash column chromatography on
silica gel, or by preparative HPLC using the general protocol
described below; NMR samples were dissolved in deuterated solvent
(CD.sub.3OD or CDCl.sub.3), and spectra were acquired with a Varian
Gemini 2000 instrument (300 MHz) under standard parameters; and
mass spectrometric identification was performed by an electrospray
ionization method (ESMS) with a Perkin Elmer instrument (PE SCIEX
API 150 EX).
[0219] Analytical HPLC: Crude compound was dissolved in 50%
MeCN/H.sub.2O (with 0.1% TFA) at 0.5-1.0 mg/mL concentration, and
analyzed using a reverse-phased analytical column (Agilent Zorbax
Bonus-RP, 2.1.times.50 mm, ID=5 .mu.m); at a flow rate of 0.5
mL/min; with 10% MeCN/H.sub.2O (0.1% TFA) as a solvent (0-0.5 min)
(10 to 70% linear gradient, 0.5-5 min); and UV detection at 214,
254, and 280 nm.
[0220] Preparative HPLC purification: Crude compound was dissolved
in 50% MeCN/H.sub.2O (with 0.1% TFA) at 30-45 mg/mL concentration,
filtered, and injected onto a reversed phase column (YMC Pack-Pro
C18, 50a.times.20 mm, ID=5 elm); with a linear solvent gradient: 10
to 60 % MeCN (0.1% TFA)/H.sub.2O (0.1% TFA) over 50 min; at a flow
rate of 40 mL/min; with UV detection at 214, 254, or 280 nm.
General Procedure A
N-Boc Protected Amino Alcohols
[0221] N-Boc-amino alcohols were prepared from the corresponding
amino alcohol by treating with di-tert-butyl-di-carbonate
((Boc).sub.2O) in CH.sub.2Cl.sub.2 or methanol under standard
conditions such as those described in the following representative
example.
[0222] To a cold solution of methanol (300 mL) containing
3-(hydroxy-methyl)piperidine (25 g, 217 mmole) cooled with ice bath
was added (Boc).sub.2O (57 g, 261 mmole) under stream of nitrogen.
The reaction mixture was stirred and allowed to warm gradually to
room temperature. After stirring overnight, the mixture was
concentrated in vacuo, yielding an oily residue that was
partitioned between EtOAc (250 mL) and 0.1 M NaOH (250 mL). The
organic phase was collected, and dried over MgSO.sub.4. The
solution was passed through silica gel column (dry volume of 200
mL), followed by rinsing with EtOAc (500 mL). The filtrates were
combined, and concentrated in vacuo, to give white crystals, which
were washed with hexanes (200 mL), and dried in air to afford
N-Boc-(3-hydroxymethyl)-piperidine (43.3 g, .about.93%).
Example 1
Preparation of Compound 1
[0223] To a stirred cold solution of THF containing
4,4'-methylene-bis(2,6-dimethylphenol) (1.54 g, 6 mmol),
N-Boc-3-pyrrolidinol (2.42 g, 13 mmol), and triphenylphosphine
(3.41 g, 13 mmol) at 0.degree. C., under nitrogen atmosphere, was
added dropwise a solution of diethylazo-dicarboxylate (DEAD; 2.05
mL, 13 mmol) in THF. The mixture was allowed to return gradually to
ambient temperature, where stirring continued for 20 hours. After
concentrating the mixture in vacuo, the residue was taken up in
dichloromethane (40 mL), and cooled to 0.degree. C. While stirring
under nitrogen atmosphere, trifluoroacetic acid (10 mL) was added
dropwise. The mixture was returned to ambient temperature and
stirred for 2 hours. The mix was then concentrated in vacuo, and
partitioned between ethyl acetate (75 mL) and IN HCl (15 mL) in a
separatory funnel. After gentle shaking, the aqueous layer was
collected, filtered, and fractionated by preparative HPLC.
Appropriate fractions of the desired product were combined and
lyophilized to afford the title compound as its TFA salt. ESMS
(C.sub.25H.sub.34N.sub.2O.sub.2)- : calcd. 394.5572; obsd. 395.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.61 min. .sup.1H-NMR (CD.sub.3OD, 299.96 MHz): .delta.
(ppm) 6.83 (s, 4H), 4.74 (m, 2H), 3.74 (s, 2H), 3.20-3.61 (m, 8H),
2.22-2.37 (m, 2H), 2.21 (s, 12H), 2.02-2.19 (m, 2H).
Example 2
Preparation of Compound 2
[0224] To a stirred, cold solution of TBF (20 mL) containing
4,4'-methylene-bis(2,6-dimethylphenol) (0.55 g, 2.15 mmol),
N-Boc-3-(hydroxymehtyl)-piperidine -(1.0 g, 4.64 mmol), and
triphenylphosphine (1.18 g, 4.50 mmol) in ice bath, was added
dropwise diethyl azodicarboxylate (DEAD; 0.79 g, 4.54 nimol) in THF
(5 mL). The mixture was stirred at 0.degree. C. for 2 hours, and
was allowed to warm to ambient temperature where it was stirred for
12 hours. After concentration in vacuo, the residue was dissolved
in EtOAc (100 mL) and washed with 0.1 M NaOH (2.times.100 mL). The
organic phase was dried over MgSO.sub.4, and concentrated in vacuo
to afford colorless oil.
[0225] Deprotection of N-Boc group of the product was performed by
treating with TFA. It was dissolved in CH.sub.2CL.sub.2 (10 mL),
cooled in ice bath, and treated slowly with CF.sub.3CO.sub.2H (10
mL) under nitrogen atmosphere. The mixture was stirred for 2 hours
in ice bath, and concentrated to oily residue. It was partitioned
between EtOAc (150 mL) and 1.0 M NaOH (150 mL). The organic phase
was dried over MgSO.sub.4, and concentrated. The resulting oily
product was purified by flash silica column chromatography, eluting
with 50% EtOAc/hexanes to 5% i-PrNH.sub.2/10% MeOH/50%
EtOAc/hexanes, to provide the title compound (540 mg). ESMS
(C.sub.29H.sub.42N.sub.2O.sub.2): calcd. 450.66; obsd. 451.4
[M+H].sup.+. Thin layer chromatography: R.sub.f=0.14 (5%
i-PrNH.sub.2/50% EtOAc/Hexanes; silica TLC).
Examples 3-12
[0226] Unless otherwise noted, compounds 3-12 were prepared using a
procedure similar to that described in Example 1, except replacing
the N-Boc-3-pyrrolidinol used therein with the requsite
alcohol.
Example 3
[0227] Compound 3 was prepared using N-Boc-4-hydroxypiperidine.
ESMS (C.sub.27H.sub.38N.sub.2O.sub.2): calcd. 422.61; obsd. 423.2
[M+H].sup.+. HPLC: Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O
over 5 min)=2.75 min.
Example 4
[0228] Compound 4 was prepared using (R)N-Boc-3-hydoxypyrrolidne.
ESMS (C.sub.25H.sub.34N.sub.2O.sub.2): calcd. 394.5572; obsd. 395.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.61 min.
Example 5
[0229] Compound 5 was prepared using (S)-N-Boc-3-hydoxypyrrolidine.
ESMS: (C.sub.25H.sub.34N.sub.2O.sub.2).calcd. 394.5572; obsd. 395.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.61 min.
Example 6
[0230] Compound 6 was prepared using
N-methyl-2-(2-hydroxyethyl)pyrrolidin- e (without treatment with
TFA). ESMS (C.sub.31H.sub.46N.sub.2O.sub.6): calcd. 478.7; obsd.
479.3 [M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O
over 5 min)=3.1 min.
Example 7
[0231] Compound 7 was prepared using
N-Boc-2-(2-hydroxyethyl)piperidine. ESMS
(C.sub.31H.sub.46N.sub.2O.sub.2): calcd. 478.7; obsd. 479.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.2 min.
Example 8
[0232] Compound 8 was prepared from the mono-adduct isolated from
the synthesis of compound 5 using N-Boc-(R)-3-pyrrolidinol. ESMS
(C.sub.25H.sub.34N.sub.2O.sub.2): calcd. 394.5572; obsd. 395.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.61 min.
Example 9
[0233] Compound 9 was prepared using N-methyl-3-hydroxypyrrolidine
(except treatment with TFA). ESMS (C.sub.27H.sub.38N.sub.2O.sub.2):
calcd. 422.611; obsd. 423.1 [M+H].sup.+. Retention time (anal.
HPLC: 10-70% MeCN/H.sub.2O over 5 min)=2.57 min.
Example 10
[0234] Compound 10 was prepared using
1-methyl-2-piperidinemethanol. ESMS
(C.sub.31H.sub.46N.sub.2O.sub.2): calcd. 478.7185; obsd. 479.4
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.09 min.
Example 11
[0235] Compound 11 was prepared using 3-hydroxyquinuclidinol. ESMS
(C.sub.31H.sub.42N.sub.2O.sub.2): calcd. 474.7; obsd. 475.2
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3 min.
Example 12
[0236] Compound 12 was prepared using N-(2-hydroxyethyl)
pyrrolidine. ESMS (C.sub.29H.sub.42N.sub.2O.sub.2): calcd. 450.7 ;
obsd. 451.1 [M+H].sup.+. Retention time (anal. HPLC: 10-70%
MeCN/H.sub.2O over 5 min)=2.8 min.
Example 13
Preparation of Compound 13
[0237] To a stirred solution of THF (30 mL) containing
N-Boc-3-piperidinyl-methanol (1.0 g, 4.65 mmol),
bis(4-hydroxy-3,5-dimeth- ylphenyl)sulfone (2.23 mmol), and
triphenylphosphine (1.34 g, 5.11 mmol) cooled in ice bath was added
diethylazadicarboxylate (0.89 g, 5.11 mmol) dropwise under nitrogen
atmosphere. The reaction mixture was stirred in ice bath, and
allowed to warm gradually to room temperature while stirred
overnight. After quenching the reaction mixture by adding 5 mL of
water, it was concentrated in vacuo. The residue was partitioned
between alkaline brine (150 mL) and EtOAc (150 mL). The organic
phase was collected, dried over Na.sub.2SO.sub.4, and evaporated in
vacuo, yielding pale red solid. It was dissolved in
CH.sub.2Cl.sub.2 (10 mL), cooled in ice bath, and treated with TFA
(10 mL) under nitrogen stream. The mixture was stirred for 2 hours
at 5.degree. C. Evaporation of the solution afforded the crude
product. After being solubilized in aqueous acetonitrile, the
mixture was purified by preparative reversed phase HPLC to provide
the title compound. Retention time (anal. HPLC: 10-70%
MeCN/H.sub.2O over 5 min)=2.8 min. ESMS
(C.sub.28H.sub.40N.sub.2O.sub.4S)- : calcd. 500.70; obsd. 501.4
[M+H].sup.+.
Examples 14-16
[0238] Compounds 14-16 were prepared using a procedure similar to
that described in
Example 13, except replacing the
bis(4-hydroxy-3,5-dimethylphenyl)sulfone used therein with the
requsite diol.
Example 14
[0239] Compound 14 was prepared using
2,2-bis(4-hydroxy-3,5-dichlorophenyl- )propane. Retention time
(anal. HPLC: 10-70% MeCN/H.sub.2O over 5 min)=3.55 min. ESMS
(C.sub.27H.sub.34N.sub.2O.sub.2Cl.sub.4): calcd. 560.39; obsd.
561.2 [M+H].sup.+.
Example 15
[0240] Compound 15 was prepared using bis(4-hydroxyphenyl)methane.
Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over 5 min)=2.8
min. ESMS (C.sub.25H.sub.34N.sub.2O.sub.2): calcd. 394.56; obsd.
395.2 [M+H].sup.+.
Example 16
[0241] Compound 16 was prepared using
4,4'-isopropylidene-bis(2,6-dimethyl- phenol). ESMS
(C.sub.31H.sub.46N.sub.2O.sub.2): calcd. 478.72; obsd. 479.1
[M+H].sup.+. HPLC: Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O
over 5 min)=3.3 min. Thin layer chromatography: R.sup.f=0.17 (5%
i-PrNH.sub.2/10% MeOH/CH.sub.2Cl.sub.2).
Example 17
Preparation of Compound 17
[0242] Compound 17 was prepared using a procedure similar to that
described in Example 2, except replacing the starting materials
used therein with 4,4'-sulfonyl-bis(2,6-dimethylphenol) and
N-Boc-4-hydroxypiperidine. ESMS (C.sub.26H.sub.36N.sub.2O.sub.4S):
calcd. 472.65; obsd. 473.4 [M+H].sup.+. HPLC: Retention time (anal.
HPLC: 10-70% MeCN/H.sub.2O over 5 min) 2.4 min.
Examples 18-26
[0243] Unless otherwise noted, compounds 18-26 were prepared using
a procedure similar to that described in Example 1, except
replacing the starting materials used therein with the starting
materials described below.
Example 18
[0244] Compound 18 was prepared from
4,4'-isopropylidenebis(2,6-dimethylph- enol) and
N-Boc-3-hydroxypyrrolidine. ESMS: (C.sub.27H.sub.38N.sub.2O.sub.-
2) calcd. 422.611; obsd. 423.4 [M+H].sup.+. Retention time (anal.
HPLC: 10-90% MeCN/H.sub.2O over 5 min)=2.60 min. .sup.1H-NMR
(CD30D, 299.96 MHz): .delta. (ppm) 6.90 (s, 4H), 4.78 (m, 2H),
3.40-3.68 (m, 8H), 2.00-2.40 (m, 16H), 1.60 (s, 6H).
Example 19
[0245] Compound 19 was prepared from 4,4'-methylene-bis(1-phenol)
and N-Boc-3-hydroxypyrrolidine. ESMS (C.sub.21H.sub.26N.sub.2O):
calcd. 338.4; obsd. 339.1 [M+H].sup.+. Retention time (anal. HPLC:
10-70% MeCN/H.sub.2O over 5 min)=2.1 min.
Example 20
[0246] Compound 20 was prepared from
4,4'-isopropylidenebis(2,6-dichloroph- enol) and
N-Boc-3-hydroxypyrrolidine. ESMS (C.sub.23H.sub.26Cl.sub.4N.sub.-
2O.sub.2): calcd. 504.2825; obsd. 505.1 [M+H].sup.+. Retention time
(anal. HPLC: 10-90% MeCN/H.sub.2O over 5 min)=2.62 min.
Example 21
[0247] Compound 21 was prepared from 4,4'-sulfonylbis(2,6
dimethylphenol) and N-Boc-3-hydroxypyrrolidine. ESMS
(C.sub.24H.sub.32N.sub.2O.sub.4S): calcd. 444.5952; obsd.
445.2[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O
over 5 min)=2.19 min.
Example 22
[0248] Compound 22 was prepared from
2,2-bis(4-hydroxy-3-methylphenyl)prop- ane and
N-Boc-3-hydroxypyrrolidine. ESMS (C.sub.25H.sub.34N.sub.2O.sub.2):
calcd. 394.6 ; obsd. 394.9 [M+H].sup.+. Retention time (anal. HPLC:
10-70% MeCN/H.sub.2O over 5 min)=2.7 min.
Example 23
[0249] Compound 23 was prepared from
1,1-bis(4-hydroxyphenyl)cyclohexane and N-Boc-3-hydroxypyrrolidine.
ESMS (C.sub.26H.sub.34N.sub.2O.sub.2): calcd. 406.6; obsd. 407.0
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.8 min.
Example 24
[0250] Compound 24 was prepared from
bis(4-hydroxy-3,5-dimethylphenyl)sulf- one and
N-methyl-3-hydroxypyrrolidine. ESMS (C.sub.26H.sub.36N.sub.2O.sub.-
4S): calcd. 472.6 ; obsd. 473.1 [M+H].sup.+. Retention time (anal.
HPLC: 10-70% MeCN/H.sub.2O over 5 min)=2.2 min.
Example 25
[0251] Compound 25 was prepared from
bis(4-hydroxy-3,5-dimethylphenyl)sulf- one and
N-methyl-3-hydroxymethylpiperidine. ESMS (C.sub.30H.sub.44N.sub.2O-
.sub.4S): calcd. 528.8 ; obsd. 529.2 [M+H].sup.+. Retention time
(anal. HPLC: 10-70% MeCN/H.sub.2O over 5 min)=2.7 min.
Example 26
[0252] Compound 26 was prepared from
bis(4-hydroxy-3,5-dimethylphenyl)sulf- one and
N-methyl-4-hydroxypiperidine. ESMS (C.sub.28H.sub.40N.sub.2O.sub.4-
S): calcd. 500.7 ; obsd. 501.3 [M+H].sup.+. Retention time (anal.
HPLC: 10-70% MeCN/H.sub.2O over 5 min)=2.4 min.
Examples 27 to 39
[0253] Unless otherwise noted, compounds 27 to 39 were prepared
similarly as described in Example 1, except replacing the
N-Boc-3-pyrrolidinol used with the requisite alcohol.
Example 27
[0254] Compound 27 was prepared using
(S)N-phthalimido-2-amino-propanol (after coupling, the phthalimide
group was deprotected by treatment with hydrazine). ESMS
(C.sub.23H.sub.34N.sub.2O.sub.2): calcd. 370.26; obsd. 371.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.688 min. .sup.1H-NMR (CD.sub.3OD, 299.96 MHz): .delta.
(ppm) 1.31 (d, impurity), 1.47 (d, 6H), 2.27 (s, 12H), 3.68-3.95
(m, 8H), 6.87 (s, 4H).
Example 28
[0255] Compound 28 was prepared using
(R)-N-phthalimido-2-amino-propanol (after coupling, the phthalimide
group was deprotected by treatment with hydrazine). ESMS
(C.sub.23H.sub.34N.sub.2O.sub.2): calcd. 370.26; obsd. 371.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.666 min. .sup.1H-NMR (CD.sub.3OD, 299.96 MHz): .delta.
(ppm) 1.31 (d, impurity), 1.47 (d, 6H), 2.27 (s, 12H), 3.68-3.95
(m, 8H), 6.87 (s, 4H).
Example 29
[0256] Compound 29 was prepared using
N,N-di-ethyl-5-amino-2-pentanol (without treatment with TFA). ESMS
(C.sub.35H.sub.58N.sub.2O.sub.2): calcd. 538.45; obsd. 539.4
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over
4-min)=3.394 min.
Example 30
[0257] Compound 30 was prepared using
N,N-di-methyl-3-amino-2,2-di-methyl-- propanol (without treatment
with TFA). ESMS (C.sub.31H.sub.50N.sub.2O.sub.- 2): calcd. 482.39;
obsd. 483.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70%
MeCN/H.sub.2O over 4 min)=3.225 min.
Example 31
[0258] Compound 31 was prepared using
N,N-di-methyl-3-amino-2-propanol (without treatment with TFA). ESMS
(C.sub.27H.sub.42N.sub.2O.sub.2): calcd. 426.32; obsd. 427.3
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=3.039 min.
Example 32
[0259] Compound 32 was prepared using 4-hydroxy-N-methyl-piperidine
(without treatment with TFA). ESMS
(C.sub.29H.sub.42N.sub.2O.sub.2): calcd. 450.6648; obsd. 451.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.80 min.
Example 33
[0260] Compound 33 was prepared using
N-methyl-piperidine-3-methanol (without treatment with TFA). ESMS
(C.sub.31H.sub.46N.sub.2O.sub.2): calcd. 478.7185; obsd. 479.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.15 min.
Example 34
[0261] Compound 34 was prepared using N-isopropyl-3-pyrrolidinol
(without treatment with TFA). ESMS
(C.sub.31H.sub.46N.sub.2O.sub.2): calcd. 478.7185; obsd. 479.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.05 min.
Example 35
[0262] Compound 35 was prepared using N-methyl-2-piperidineethanol
(without treatment with TFA). ESMS
(C.sub.33H.sub.50N.sub.2O.sub.2): calcd. 506.7723; obsd. 507.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.22 min.
Example 36
[0263] Compound 36 was prepared using N,N-dimethylethanolamine
(without treatment with TFA). ESMS
(C.sub.25H.sub.38N.sub.2O.sub.2): calcd. 398.589; obsd. 399.0
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.65 mm.
Example 37
[0264] Compound 37 was prepared using N,N-diethylethanolamine
(without treatment with TFA). ESMS
(C.sub.29H.sub.46N.sub.2O.sub.2): calcd. 454.6965; obsd. 455.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.05 min.
Example 38
[0265] Compound 38 was prepared using 4-(2-hydroxyethyl)-morpholine
(without treatment with TFA). ESMS
(C.sub.29H.sub.42N.sub.2O.sub.4): calcd. 482.6636; obsd. 483.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min) 2.76 min.
Example 39
[0266] Compound 39 was prepared using
N-Boc4-(R)-hydroxy-(L)-proline methyl ester. ESMS
(C.sub.29H.sub.38N.sub.2O.sub.6): calcd. 510.6306; obsd. 511.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.85 min.
Examples 40 to 48
[0267] Compounds 40 to 48 were prepared using a procedure similar
to that described in Example 1. Specific changes to the synthetic
procedures are described below.
Example 40
[0268] To a 0.degree. C. solution of N-Boc-3-pyrrolidinol (37.5
mmol), 4,4'-methylene-bis(2,6-dimethylphenol) (25 mmol), and
triphenylphosphine (37.5 mmol) in THF, under nitrogen atmosphere,
was added diethyl azodicarboxylate (DEAD; 37.5 mmol) dropwise over
10 mins. After the ice bath was allowed to warm to rt, the reaction
mixture was stirred at rt for 16 hrs. The mixture was then
concentrated in vacuo, and then purified by silica gel
chromatography (10:90 Ethyl Acetate: DCM), which afforded a mono
ether adduct as a product. This intermediate was used as a reactant
in next reaction.
[0269] To a 0.degree. C. solution of
N-isopropyl-3-hydroxypyrrolidine (25 mmol), the intermediate (10
mmol), and triphenylphosphine (25 mmol) in THF, under a nitrogen
atmosphere, was added DEAD (25 mmol) dropwise over 10 mins. The
reaction mixture was stirred at 0.degree. C. for 4 hrs and at rt
for 16 hrs. After concentrated, the mixture was taken up in 50 mL
of DCM, chilled to 0.degree. C., and followed by addition of 10 mL
of TFA. The mix was stirred for 2 hrs, and concentrated in vacuo.
The residue was taken up in 75 mL of Ethyl Acetate, and extracted
into 20 mL of 1N HCl. The aqueous layer was collected, and purified
by prep HPLC to afford Compound 40. ESMS
(C.sub.28H.sub.40N.sub.2O.sub.2): calcd. 436.6379; obsd. 437.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.82 min.
Example 41
[0270] Compound 41 was prepared similarly as described for compound
40 except replacing N-isopropyl-3-pyrrolidinol with
N-methyl-3-pyrrolidinol. ESMS (C.sub.26H.sub.36N.sub.2O.sub.2):
calcd. 408.5841; obsd. 409.2 [M+H].sup.+. Retention time (anal.
HPLC: 10-70% MeCN/H.sub.2O over 5 min) 2.69 min.
Example 42
[0271] Paraformaldehyde (54 mg, 1.8 mmol) was added to a solution
of compound 5 (AMI 7778) (186.8 mg) in ethanol before the mixture
was heated at 100.degree. C. for 30 mins. The mixture was cooled to
ambient temperature and solid sodium cyanoborohydride (75.6 mg, 1.2
mmol) was added in portions. The mixture was stirred for 2 hrs at
ambient temperature, and then quenched with water. The solution was
concentrated under reduced pressure, and purified by prep HPLC to
give compound 42. ESMS (C.sub.27H.sub.38N.sub.2O.sub.2): calcd.
422.611; obsd. 423.1 [M+H].sup.+. Retention time (anal. HPLC:
10-70% MeCN/H.sub.2O over 5 min)=2.64 min.
Example 43
[0272] First, N-benzyl-pyrrolidine-3-methanol was prepared as
follows. Methyl N-benzyl-5-oxo-pyrrolidine-3-carboxylate (11.66 g,
50 mmol) was dissolved in diethyl ether and cooled to 0.degree. C.
This solution was added to a 0.degree. C. suspension of lithium
aluminum hydride in diethyl ether under nitrogen atmosphere. After
addition, the mixture was refluxed for 1 hr. and then cooled with
an ice bath. To quench the reaction, sodium sulfate decahydrate was
added and the mixture was stirred for 1 hr. After filtration, the
filtrate was collected, and concentrated to dryness to give
N-Benzyl-pyrrolidine-3-methanol. ESMS (C.sub.12H.sub.17NO): calcd.
191.13; obsd. 192-2 [M+H].sup.+.
[0273] Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over 5
min)=0.95 min.
[0274] To a 0.degree. C. solution of the
N-Benzyl-pyrrolidine-3-methanol (25 mmol),
4,4'-methylene-bis(2,6-dimethylphenol) (10 mmol), and
triphenylphosphine (25 mmol) in THF, under nitrogen atmosphere, was
added diethyl azodicarboxylate (DEAD; 25 mmol) dropwise over 10
mins. The reaction mixture was warmed up gradually to rt over 4 hr,
and stirred for additional 16 hrs. The mixture was then
concentrated in vacuo, and taken up in 35 mL of ethanol prior to
being placed in a Parr bottle. To this solution was added wet PdOH
(1 g, 20% by weight), and followed by addition of 5 mL of 6N HCl.
This mixture was shaken under a 50 psi atmosphere of hydrogen for 6
days, filtered through celite, and concentrated under reduced
pressure. The resulting residue was then taken up in 75 mL of ethyl
acetate and extracted into 20 mL of 1N HCl. The aqueous solution
was collected, and purified by prep HPLC to afford compound 43.
ESMS (C.sub.27H.sub.38N.sub.2O.sub.2): calcd. 422.611; obsd. 423.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.95 min.
Example 44
[0275] To a 0.degree. C. solution of N-Boc4-(R)-hydroxy-(L)-proline
methyl ester (150 mmol), 4,4'-methylene-bis-(2,6-dimethylphenol)
(50 mmol), and triphenylphosphine (150 mmol) in THF, under nitrogen
atmosphere, was added diethyl azodicarboxylate (DEAD; 150 mmol)
dropwise over 20 mins. The reaction mixture was warmed up gradually
to rt over 4 hrs, and stirred at rt for additional 16 hrs. The
mixture was then concentrated and purified by silica gel
chromatography (DCM:EtOAc 95:5) to afford an intermediate di-ester
(1). ESMS (C.sub.39H.sub.54N.sub.2O.sub.10): calcd. 710.38; obsd.
711.5 [M+H].sup.+. Retention time (anal. HPLC: 25-95% MeCN/H.sub.2O
over 5 min)=4.95 min.
[0276] The intermediate I (5.7 g, 8.02 mmol) was dissolved in TBF,
and placed in a nitrogen atmosphere before dropwise addition of
lithium borohydride in THF (2.0 M, 12.03 mL, 24.0 6 mmol). The
mixture was stirred for 15 hrs, then concentrated in vacuo, and
taken up in ethyl acetate. It was washed with phosphoric acid,
saturated sodium bicarbonate, and brine. After dried over sodium
sulfate and filtered, the organic phase was concentrated to dryness
to give an intermediate alcohol (II). ESMS
(C.sub.37H.sub.54N.sub.2O.sub.8): calcd. 654.39; obsd. 655.1
[M+H].sup.+. Retention time (anal. HPLC: 25-95% MeCN/H.sub.2O over
5 min)=4.60 min.
[0277] To the intermediate 11 (521 mg, 0.8 mmol) dissolved in DCM,
under nitrogen atmosphere, was added triethylamine (446 uL, 2.4
mmol) and then methanesulfonylchloride (186 uL, 2.4 mmol) in DCM.
The mixture was stirred for 15 hrs, and then concentrated in vacuo.
It was taken up in ethyl acetate, and washed with phosphoric acid,
saturated sodium bicarbonate, and brine. After dried over sodium
sulfate, and filtered, the organic phase was concentrated to
dryness to give an intermediate sulfonate (II). ESMS
(C.sub.39H.sub.58N.sub.2O.sub.12S.sub.2): calcd. 810.34; obsd.
811.5 [M+H].sup.+. Retention time (anal. HPLC: 25-95% MeCN/H.sub.2O
over 5 min)=5.0 min.
[0278] To the intermediate III (6.4 g, 7.9 mmol) dissolved in THF,
under nitrogen atmosphere, was added dropwise a solution of lithium
triethylborohydride in TBF (1.0 M, 80 mL, 80 mmol). The mixture was
stirred for 15 hrs, and concentrated. The residue was taken up in
50 mL of dichloromethane, and chilled to 0.degree. C. prior to
addition of 10 mL of TFA. The mixture was stirred for 2 hrs,
concentrated in vacuo, and taken up in 75 mL of Ethyl Acetate. It
was extracted with 20 mL of 1N HCl. The aqueous layer was
collected, and purified by prep HPLC to afford compound 44. ESMS
(C.sub.27H.sub.38N.sub.2O.sub.2): calcd. 422.611; obsd. 423.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.90 min.
Example 45
[0279] To a solution of the intermediate ester (I)--which was used
in synthesis of compound 44--(3.43 g, 4.83 mmol) in methanol was
added a solution of NaOH (1.16 g, 29 mmol) in methanol (total
methanol volume was 20 mL). The mixture was stirred for 4 hrs, and
concentrated under reduced pressure. The residue was dissolved in
water and stirred while 6N HCl was added dropwise until
precipitates were formed (pH=6). It was collected and dried under
vacuum to give N-Boc derivative of compound 45. ESMS
(C.sub.37H.sub.50N.sub.2O.sub.10): calcd. 682.35; obsd. 683.0
[M+H].sup.+. Retention time (anal. HPLC: 25-95% MeCN/H.sub.2O over
5 min)=4.20 min.
[0280] The N-Boc intermediate (683 mg, 1 mmol) was taken up in 10
mL of dichloromethane, and-cooled to 0.degree. C. before addition
of 7.5 mL of TFA. The mixture was stirred for 2 hrs, and
concentrated in vacuo. It was taken up in 75 mL of Ethyl Acetate,
and extracted with 20 mL of 1N HCl. The aqueous solution was
purified by prep HPLC to afford compound 45. ESMS
(C.sub.27H.sub.34N.sub.2O.sub.6): calcd. 482.6636; obsd. 483.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.0 over 5
min)=2.62 min.
Example 46
[0281] A solution of the N-Boc derivative of compound 45 (683 mg, 1
mmol), HOAT (340 mg, 2.5 mmol), HATU (950 mg, 2.5 mmol),
diisopropylethylamine (540 uL, 3.0 mmol), and dimethylamine (2.0 M,
1.25 mL, 2.5 mmol) in DMF was stirred for 16 hrs, and then
concentrated in vacuo. It was taken up in 50 mL of dichloromethane,
and cooled to 0.degree. C., before addition of 10 mL of TFA. After
stirred for 2 hrs, the mixture was concentrated under reduced
pressure, and taken up in 75 mL of Ethyl Acetate. It was extracted
with 20 mL of 1N HCl, and the aqueous solution was purified by prep
HPLC to afford compound 46. ESMS (C.sub.31H.sub.44N.sub.4O.sub.4):
calcd. 536.7149; obsd. 537.2 [M+H].sup.+. Retention time (anal.
HPLC: 10-70% MeCN/H.sub.2O over 5 min)=2.75 min.
Example 47
[0282] To a cold solution of the intermediate alcohol 11 (655 mg, 1
mmol)--used in synthesis of compound 44--in 10 mL of
dichloromethane at 0.degree. C. was added 7.5 mL of TFA. The
mixture was stirred for 2 hrs, and concentrated in vacuo. The
residue was taken up in 75 mL of Ethyl Acetate, and extracted with
20 mL of 1N HCl. The aqueous solution was collected, and purified
by prep HPLC to afford compound 47. ESMS
(C.sub.27H.sub.38N.sub.2O.sub.4): calcd. 454.6098; obsd. 455.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.86 min.
Example 48
[0283] To a cold solution of the intermediate alcohol II (655 mg, 1
mmol)--used in synthesis of compound 44--and methyl iodide (426 mg,
3 mmol) in THF at 0.degree. C. was added sodium hydride (60%, 240
mg, 6 mmol). After the addition, the mixture was stirred at rt for
16 hrs, and quenched with wet THF. The mixture was partitioned
between ethyl acetate and water. The organic phase was washed with
saturated sodium bicarbonate, and brine. After dried over sodium
sulfate, and filtered, the filtrate was concentrated under reduced
pressure. The residue was taken up in 10 mL of dichloromethane, and
chilled to 0.degree. C., before treatment with 7.5 mL of TFA. The
mixture was stirred for 2 hrs, then concentrated, and taken up in
75 mL of Ethyl Acetate. It was extracted with 20 mL of 1N HCl, and
the aqueous solution was purified by prep HPLC to afford compound
48. ESMS (C.sub.29H.sub.42N.sub.2O.sub.4): calcd. 482.6636; obsd.
483.3 [M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O
over 5 min)=2.99 min.
Example 49
[0284] Compound 49 was prepared similarly as described in Example
1, except replacing 4,4'-methylene-bis(2,6-dimethylphenol) and the
N-Boc-3-pyrrolidinol used with 4,4'-methylene-bisphenol and
N-isopropyl-3-pyrrolidinol (without treatment with TFA). ESMS
(C.sub.27H.sub.38N.sub.2O.sub.2): calcd. 422.61; obsd. 423.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.50 min.
Example 50
[0285] Compound 50 was prepared similarly as described in Example
1, except replacing 4,4'-methylene-bis(2,6-dimethylphenol) and the
N-Boc-3-pyrrolidinol used with
4,4'-isopropylidene-bis(2,6-dimethylphenol- ) and
N-methyl-3-pyrrolidinol, respectively (without treatment with TFA).
ESMS (C.sub.29H.sub.42N.sub.2O.sub.2): calcd. 450.6648; obsd. 451.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O -over
5 min)=2.85 min.
Examples 51 to 58
[0286] Unless otherwise noted, compounds 51 to 58 were prepared
similarly as described in Example 1, except replacing
4,4'-methylene-bis(2,6-dimeth- ylphenol) and the
N-Boc-3-pyrrolidinol used with 4,4'-isopropylidene(2-met-
hylphenol) and the requisite alcohol.
Example 51
[0287] Compound 51 was prepared using N-(2-hydroxyethyl)morpholine
(without treatment with TFA). ESMS
(C.sub.29H.sub.42N.sub.2O.sub.4): calcd. 482.31; obsd. 483.3
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.860 min.
Example 52
[0288] Compound 52 was prepared using
N,N-di-ethyl-5-amino-2-pentanol (without treatment with TFA). ESMS
(C.sub.35H.sub.58N.sub.2O.sub.3): calcd. 538.45; obsd. 539.4
[M+H].sup.+. Retention time (anal. HPLC: 20-90% MeCN/H.sub.2O over
4 min)=2.619 min.
Example 53
[0289] Compound 53 was prepared using
N,N-di-methyl-3-amino-2,2-di-methyl-- propanol (without treatment
with TFA). ESMS (C.sub.31H.sub.50N.sub.2O.sub.- 2): calcd. 482.39;
obsd. 483.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70%
MeCN/H.sub.2O over 4 min)=3.472 min.
Example 54
[0290] Compound 54 was prepared using N-methyl-4-hydroxypiperidine
(without treatment with TFA). ESMS
(C.sub.29H.sub.42N.sub.2O.sub.2): calcd. 450.32; obsd. 451.3
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.985 min.
Example 55
[0291] Compound 55 was prepared using
N-methyl-3-hydroxymethylpiperidine (without treatment with TFA).
ESMS (C.sub.31H.sub.46N.sub.2O.sub.2): calcd. 478.36; obsd. 479.3
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=3.361 min.
Example 56
[0292] Compound 56 was prepared using
N,N-di-methyl-3-amino-2-propanol (without treatment with TFA). ESMS
(C.sub.27H.sub.42N.sub.2O.sub.2): calcd. 426.32; obsd. 427.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min) 3.103 min.
Example 57
[0293] Compound 57 was prepared using
N-methyl-2-hydroxymethylpiperidine (without treatment with TFA).
ESMS (C.sub.31H.sub.46N.sub.2O.sub.2): calcd. 478.36; obsd. 479.3
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=3.296 min.
Example 58
[0294] Compound 58 was prepared using N-methyl-3-pyrrolidinol
(without treatment with TFA). ESMS
(C.sub.27H.sub.38N.sub.2O.sub.2): calcd. 422.61; obsd. 423.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.79 min.
Example 59
[0295] Compound 59 was prepared similarly as described in Example
1, except replacing 4,4'-methylene-bis(2,6-dimethylphenol) and the
N-Boc-3-pyrrolidinol used with 1,1-bis(4-hydroxyphenyl)cyclohexane
and N-methyl-3-pyrrolidinol, respectively (without treatment with
TFA). ESMS (C.sub.28H.sub.38N.sub.2O.sub.2): calcd. 434.622; obsd.
435.2 [M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O
over 5 min)=2.90 min.
Examples 60 to 71
[0296] Unless otherwise noted, compounds 60 to 71 were prepared
similarly as described in Example 1, except replacing
4,4'-methylene-bis(2,6-dimeth- ylphenol) and the
N-Boc-3-pyrrolidinol used with 1,2-bis(3,5-dimethyl-4-hy-
droxyphenyl)ethane and the requisite alcohol.
Example 60
[0297] Compound 60 was prepared using N-(2-hydroxyethyl)morpholine
(without treatment with TFA). ESMS
(C.sub.30H.sub.44N.sub.2O.sub.4): calcd. 496.33; obsd. 497.2
[M+H].sup.+. Retention time (anal. DPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.928 mm.
Example 61
[0298] Compound 61 was prepared using
N,N-di-methyl-3-amino-2-propanol (without treatment with TFA). ESMS
(C.sub.28H.sub.44N.sub.2O.sub.2): calcd. 440.34; obsd.; 441.3
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=3.037 min.
Example 62
[0299] Compound 62 was prepared using
N-methyl-2-(2-hydroxyethyl)pyrrolidi- ne (without treatment with
TFA). ESMS (C.sub.32H.sub.48N.sub.2O.sub.2): calcd. 492.37; obsd.
493.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=3.357 min.
Example 63
[0300] Compound 63 was prepared using N-Boc-3-hydroxypyrrolidine.
ESMS (C.sub.26H.sub.36N.sub.2O.sub.2): calcd. 408.58; obsd. 409.2
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.8 min.
Example 64
[0301] Compound 64 was prepared using N-methyl-3-hydroxypyrrolidine
(without treatment with TFA). ESMS
(C.sub.28H.sub.40N.sub.2O.sub.2): calcd. 436.64; obsd. 437.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.85 min.
Example 65
[0302] Compound 65 was prepared using N-Boc4-hydroxypiperidine.
ESMS (C.sub.28H.sub.40N.sub.2O): calcd. 436.64; obsd. 437.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.9 min.
Example 66
[0303] Compound 66 was prepared using
N-Boc-3-hydroxymethylpiperidine. ESMS
(C.sub.30H.sub.44N.sub.2O.sub.2): calcd. 464.69; obsd. 465.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.25 min.
Example 67
[0304] Compound 67 was prepared using 4-hydroxy-N-methyl-piperidine
(without treatment with TFA). ESMS (C.sub.30H.sub.44N.sub.2O):
calcd. 464.6916; obsd. 465.3 [M+H].sup.+. Retention time (anal.
HPLC: 10-70% MeCN/H.sub.2O over 5 min)=2.99 min.
Example 68
[0305] Compound 68 was prepared using
N-methyl-piperidine-3-methanol (without treatment with TFA). ESMS
(C.sub.32H.sub.48N.sub.2O): calcd. 492.7454; obsd. 493.2
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.25 min.
Example 69
[0306] Compound 69 was prepared using N-methyl-2-piperidineethanol
(without treatment with TFA). ESMS
(C.sub.32H.sub.52N.sub.2O.sub.2): calcd. 520.7992; obsd. 521.4
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.40 mm.
Example 70
[0307] Compound 70 was prepared using
N-methyl-piperidine-2-methanol (without treatment with TFA). ESMS
(C.sub.32H.sub.48N.sub.2O.sub.2): calcd. 492.7454; obsd. 493.2
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.22 min.
Example 71
[0308] Compound 71 was prepared using
N-(2-hydroxyethyl)-pyrrolidine (without treatment with TFA). ESMS
(C.sub.30H.sub.44N.sub.2O.sub.2): calcd. 464.6916; obsd. 465.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.02 min.
Examples 72 to 75
[0309] Unless otherwise noted, compounds 72 to 75 were prepared
similarly as described in Example 1, except replacing
4,4'-methylene-bis(2,6-dimeth- ylphenol) and the
N-Boc-3-pyrrolidinol used with 2,6-dimethyl-4-(2-hydroxy-
-3-methylbenzyl)phenol and the requisite alcohol.
Example 72
[0310] Compound 72 was prepared using N-methyl-3-pyrrolidinol
(without treatment with TFA). ESMS
(C.sub.26H.sub.36N.sub.2O.sub.2): calcd. 408.5841; obsd. 409.2
[M+H].sup.+. Retention time (anal. HPLC: 25-95% MeCN/H.sub.2O over
5 min) 2.54 min.
Example 73
[0311] Compound 73 was prepared using
N-methyl-piperidine-3-methanol (without treatment with TFA). ESMS
(C.sub.30H.sub.44N.sub.2O.sub.2): calcd. 464.6916; obsd. 465.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.09 min.
Example 74
[0312] Compound 74 was prepared using N-methyl-4-hydroxy-piperidine
(without treatment with TFA). ESMS
(C.sub.28H.sub.40N.sub.2O.sub.2): calcd. 436.6379; obsd. 437.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.89 min.
Example 75
[0313] Compound 75 was prepared using N-methyl-2-piperidineethanol
(without treatment with TFA). ESMS
(C.sub.32H.sub.42N.sub.2O.sub.2): calcd. 492.7294; obsd. 493.2
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.20 min.
Examples 76 to 83
[0314] Unless otherwise noted, compounds 76 to 83 were prepared
similarly as described in Example 1, except replacing
4,4'-methylene-bis(2,6-dimeth- ylphenol) and the
N-Boc-3-pyrrolidinol used with 4-(2-hydroxybenzyl)phenol and the
requisite alcohol.
Example 76
[0315] Compound 76 was prepared using N-methyl-3-hydroxypyrrolidine
(without treatment with TFA). ESMS
(C.sub.23H.sub.30N.sub.2O.sub.2): calcd. 366.23; obsd. 367.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.485 min.
Example 77
[0316] Compound 77 was prepared using N-(2-hydroxyethyl)morpholine
(without treatment with TFA). ESMS
(C.sub.25H.sub.34N.sub.2O.sub.4): calcd. 426.25; obsd. 427.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.466 min.
Example 78
[0317] Compound 78 was prepared using
N,N-di-methyl-3-amino-2,2-di-methyl-- propanol (without treatment
with TFA). ESMS (C.sub.27H.sub.42N.sub.2O.sub.- 2): calcd. 426.32;
obsd. 427.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70%
MeCN/H.sub.2O over 4 min)=2.913 min.
Example 79
[0318] Compound 79 was prepared using N-methyl-4-hydroxypiperidine
(without treatment with TFA). ESMS
(C.sub.25H.sub.34N.sub.2O.sub.2): calcd. 394.26; obsd. 395.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.653 min.
Example 80
[0319] Compound 80 was prepared using
N-methyl-3-hydroxymethylpiperidine (without treatment with TFA).
ESMS (C.sub.27H.sub.38N.sub.2O.sub.2): calcd. 422.29; obsd. 423.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.856 min.
Example 81
[0320] Compound 81 was prepared using
N-methyl-2-(2-hydroxyethyl)piperidin- e (without treatment with
TFA). ESMS (C.sub.29H.sub.42N.sub.2O.sub.2): calcd. 450.32; obsd.
451.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=2.913 min.
Example 82
[0321] Compound 82 was prepared using
N-methyl-2-(2-hydroxyethyl)pyrrolidi- ne (without treatment with
TFA). ESMS (C.sub.27H.sub.38N.sub.2O.sub.2): calcd. 422.29; obsd.
423.2 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=2.919 min.
Example 83
[0322] Compound 83 was prepared using
N-methyl-2-hydroxymethylpiperidine (without treatment with TFA).
ESMS (C.sub.27H.sub.38N.sub.2O.sub.2): calcd. 422.29; obsd. 423.3
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.902 min.
Examples 84 to 90
[0323] Unless otherwise noted, compounds 84 to 90 were prepared
similarly as described in Example 1, except replacing
4,4'-methylene-bis(2,6-dimeth- ylphenol) and the
N-Boc-3-pyrrolidinol used with 3,3'-dihydroxydiphenylami- ne and
the requisite alcohol, respectively.
Example 84
[0324] Compound 84 was prepared using N-methyl-3-hydroxypyrrolidine
(without treatment with TFA). ESMS
(C.sub.22H.sub.29N.sub.2O.sub.3): calcd. 367.23; obsd. 368.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.339 min.
Example 85
[0325] Compound 85 was prepared using N-(2-hydroxyethyl)morpholine
(without treatment with TFA). ESMS
(C.sub.24H.sub.33N.sub.3O.sub.4): calcd. 427.25; obsd. 428.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.280 min.
Example 86
[0326] Compound 86 was prepared using
N,N-di-methyl-3-amino-2,2-di-methyl-- propanol (without treatment
with TFA). ESMS (C.sub.26H.sub.41N.sub.3O.sub.- 2): calcd. 427.32;
obsd. 428.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70%
MeCN/H.sub.2O over 4 min)=2.789 min.
Example 87
[0327] Compound 87 was prepared using N-methyl-4-hydroxypiperidine
(without treatment with TFA). ESMS
(C.sub.24H.sub.33N.sub.3O.sub.2): calcd. 395.26; obsd. 396.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.507 min.
Example 88
[0328] Compound 88 was prepared using
N-methyl-2-(2-hydroxyethyl)piperidin- e (without treatment with
TFA). ESMS (C.sub.28H.sub.41N.sub.3O.sub.2): calcd. 451.32; obsd.
452.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=2.784 min.
Example 89
[0329] Compound 89 was prepared using
N-methyl-2-(2-hydroxyethyl)pyrrolidi- ne (without treatment with
TFA). ESMS (C.sub.26H.sub.37N.sub.3O.sub.2): calcd. 423.29; obsd.
424.2 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=2.780 min.
Example 90
[0330] Compound 90 was prepared using
N-methyl-2-hydroxymethylpiperidine (without treatment with TFA).
ESMS (C.sub.26H.sub.37N.sub.3O.sub.2): calcd. 423.29; obsd. 424.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.645 min.
Examples 91 to 99
[0331] Unless otherwise noted, compounds 91 to 99 were prepared
similarly as described in Example 1, except replacing
4,4'-methylene-bis(2,6-dimeth- ylphenol) and the
N-Boc-3-pyrrolidinol used with 2,2'-methylene-bis(4-chlo- rophenol)
and the requisite alcohol.
Example 91
[0332] Compound 91 was prepared using N-Boc-3-hydroxypyrrolidine.
ESMS (C.sub.21H.sub.24Cl.sub.2N.sub.2O.sub.2):.calcd. 406.12; obsd.
407.0 [M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O
over 5 min)=2.836 min. .sup.1H-NMR (CD.sub.3OD, 299.96 MHz):
.delta. (ppm) 1.25 (s, impurity) 2.30 (m, 4H), 3.57 (m, 8H), 3.94
(m, 2H), 5.18 (s, 2H), 6.96 (d, 2H), 7.11 (s, 2H), 7.20 (dd,
2H).
Example 92
[0333] Compound 92 was prepared using N-methyl-4-hydroxypiperidine
(without treatment with TFA). ESMS
(C.sub.25H.sub.32Cl.sub.2N.sub.2O.sub.- 2): calcd. 462.18; obsd.
463.1 [M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O
over 5 min)=2.949 min. .sup.1H-NMR (CD.sub.3OD, 299.96 MHz):
.delta. (ppm) 1.33 (m, 11) 1.88 (m, 1H), 2.13 (s, 6H), 2.89 (m,
6H), 3.16 (t, 2H), 3.36 (m, 4H), 3.58 (m, 2H), 4.00 (d, 2H), 4.71
(m, 2H), 7.10 (m, 6H)
Example 93
[0334] Compound 93 was prepared using
N-methyl-3-hydroxymethylpiperidine (without treatment with TFA).
ESMS (C.sub.27H.sub.36Cl.sub.2N.sub.2O.sub.- 2): calcd. 490.22;
obsd. 491.0 [M+H].sup.+. Retention time (anal. HPLC: 10-70%
MeCN/H.sub.2O over 5 min)=3.197 min. .sup.1H-NMR (CD.sub.3OD,
299.96 MHz): .delta. (ppm) 1.35 (s, impurity) 1.78-2.10 (m, 6H),
2.33 (m, 2H), 2.79 (t, 211), 2.89 (t, 2H), 2.89 (s, 6H), 3.49 (q,
4H), 3.98 (m, 6H), 6.98 (d, 2H), 7.10 (s, 2H), 7.29 (dd, 2H).
Example 94
[0335] Compound 94 was prepared using
N-Boc-2-(2-hydroxyethyl)piperidine. ESMS
(C.sub.27H.sub.36Cl.sub.2N.sub.2O.sub.2): calcd. 490.22; obsd.
491.0 [M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O
over 5 min)=3.283 min. .sup.1H-NMR (CD.sub.3OD, 299.96 MHz):
.delta. (ppm) 1.28 (s, impurity) 1.53 (t, 41), 1.68 (m, 2H), 1.90
(m, 4H), 2.01 (m, 4H), 2.18 (m, 2H), 2.93 (t, 2H), 3.15 (s, 2H),
3.39 (m, 2H), 3.94 (s, 2H), 4.34 (t, 4H), 6.98 (m, 4H), 7.27 (dd,
2H).
Example 95
[0336] Compound 95 was prepared using N-methyl-3-hydroxypiperidine
(without treatment with TFA). ESMS
(C.sub.23H.sub.28Cl.sub.2N.sub.2O.sub.- 2): calcd. 434.15; obsd.
434.9 [M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O
over 5 min)=2.846 min.
Example 96
[0337] Compound 96 was prepared using
(S)-N-phthalimido-2-amino-propanol (after coupling, the phthalimide
group was deprotected by treatment with hydrazine). ESMS
(C.sub.19H.sub.24Cl.sub.2N.sub.2O.sub.2): calcd. 382.12; obsd.
382.8 [M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O
over 5 min)=2.934 min. .sup.1H-NMR (CD.sub.3OD, 299.96 MHz):
.delta. (ppm) 1.24(d, impurity), 1.39 (d, 6H) 3.73 (m, 2H),
4.06-4.31 (m, 6H), 7.10 (d, 4H), 7.31 (dd, 2H).
Example 97
[0338] Compound 97 was prepared using
N,N-di-methyl-3-amino-2,2-dimethyl-p- ropanol (without treatment
with TFA). ESMS (C.sub.27H.sub.40Cl.sub.2N.sub.- 2O.sub.2): calcd.
495.25; obsd. 495.4 [M+H].sup.+. Retention time (anal. HPLC: 10-70%
MeCN/H.sub.2O over 5 min)=3.260 min. .sup.1H-NMR (CD.sub.3OD,
299.96 MHz): .delta. (ppm) 1.20 (s, 12H) 2.91 (s, 12H), 3.16 (s,
4H), 3.91 (s, 4H), 4.05 (s, 211), 7.02 (m, 4H), 7.31 (dd, 2H).
Example 98
[0339] Compound 98 was prepared using N,N-di-ethyl-3-amino-propanol
(without treatment with TFA). ESMS
(C.sub.23H.sub.34N.sub.2O.sub.2): calcd. 494.25; obsd. 495. 4
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.207 min. .sup.1H-NMR (CD.sub.3OD, 299.96 MHz): .delta.
(ppm) 1.28 (t, 12H), 2.18 (m, 4H), 3.23 (q, 12H), 3.96 (s, 2H),
4.13 (t, 4H), 6.99 (m, 411), 7.28 (dd, 2H).
Example 99
[0340] Compound 99 was prepared using
N-Boc-3-hydroxymethylpiperidine-ESMS
(C.sub.25H.sub.32Cl.sub.2N.sub.2O.sub.2): calcd. 462.18; obsd.
463.1 [M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O
over 5 min)=3.221 min. .sup.1H-NMR (CD.sub.3OD, 299.96 MHz):
.delta. (ppm) 1.32-1.51 (m, 2H), 1.67-2.04 (m, 6H), 2.29 (m, 2H),
2.68-2.96 (m, 4H), 3.38 (m, 4H), 3.85-4.04 (m, 6H), 6.96 (d, 2H),
7.04 (d, 2H), 7.22 (dd, 2H).
Examples 100 to 109
[0341] Unless otherwise noted, compounds 100 to 109 were prepared
similarly as described in Example 1, except replacing
4,4'-methylene-bis(2,6-dimethylphenol) and the N-Boc-3-pyrrolidinol
used with 3,3'-ethylenedioxydiphenol and the requisite alcohol,
respectively.
Example 100
[0342] Compound 100 was prepared using N-Boc-3-hydroxypyrrolidine.
ESMS (C.sub.22H.sub.28N.sub.2O.sub.4): calcd. 384.20; obsd. 385.0
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.151 min.
Example 101
[0343] Compound 101 was prepared using N-methyl-4-hydroxypiperidine
(without treatment with TFA). ESMS
(C.sub.26H.sub.36N.sub.2O.sub.4): calcd. 440.27; obsd. 441.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.402 min.
Example 102
[0344] Compound 102 was prepared using
N-methyl-3-hydroxymethylpiperidine (without treatment with TFA).
ESMS (C.sub.28H.sub.40N.sub.2O.sub.4): calcd. 468.30; obsd. 496.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.664 min. .sup.1H-NMR (CD.sub.3OD, 299.96 MHz): .delta.
(ppm) 1.28 (s, impurity) 1.48 (m, 2H), 1.84-2.11 (m, 611), 2.38 (m,
2H), 2.91 (s, m, 6H, 4H), 3.56 (d, 2H), 3.69 (d, 2H), 3.90 (m, 2H),
4.00 (dd, 2H), 4.33 (s, 4H), 6.57 (m, 6H), 7.22 (t, 2H)
Example 103
[0345] Compound 103 was prepared using
N-Boc-2-(2-hydroxyethyl)piperidine. ESMS
(C.sub.28H.sub.40N.sub.2O.sub.4): calcd. 468.30; obsd. 469.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.801 min.
Example 104
[0346] Compound 104 was prepared using
N-methyl-3-hydroxypyrrolidine (without treatment with TFA). ESMS
(C.sub.24H.sub.32N.sub.2O.sub.4): calcd. 412.24; obsd. 413.1
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.496 min.
Example 105
[0347] Compound 105 was prepared using N-(2-hydroxyethyl)morpholine
(without treatment with TFA). ESMS
(C.sub.26H.sub.36N.sub.2O.sub.6): calcd. 472.26; obsd. 473.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.647 min.
Example 106
[0348] Compound 106 was prepared using
N,N-di-methyl-3-amino-2,2-di-methyl- -propanol (without treatment
with TFA). ESMS (C.sub.28H.sub.44N.sub.2O.sub- .4): calcd. 472.33;
obsd. 473.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70%
MeCN/H.sub.2O over 4 min)=2.935 min.
Example 107
[0349] Compound 107 was prepared using
N-methyl-2-(2-hydroxyethyl)piperidi- ne (without treatment with
TFA). ESMS (C.sub.30H.sub.44N.sub.2O.sub.4): calcd. 496.33; obsd.
497.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=3.046 min.
Example 108
[0350] Compound 108 was prepared using
N-methyl-2-(2-hydroxyethyl)pyrrolid- ine (without treatment with
TFA). ESMS (C.sub.28H.sub.40N.sub.2O.sub.4): calcd. 468.30; obsd.
469.2 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=2.819 min.
Example 109
[0351] Compound 109 was prepared using
N-methyl-2-hydroxymethylpiperidine (without treatment with TFA).
ESMS (C.sub.28H.sub.40N.sub.2O.sub.4): calcd. 468.30; obsd. 469.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.928 min.
Examples 110 to 113
[0352] Unless otherwise noted, compounds 110 to 113 were prepared
similarly as described in Example 1, except replacing
4,4'-methylene-bis(2,6-dimethylphenol) and the N-Boc-3-pyrrolidinol
used with 4,4'-(1,2-diethylethylene)diphenol and the requisite
alcohol.
Example 110
[0353] Compound 110 was prepared using N-Boc-3-hydroxypyrrolidine.
ESMS (C.sub.26H.sub.36N.sub.2O.sub.2): calcd. 408.28; obsd. 409.2
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min) 2.780 min.
Example 111
[0354] Compound 111 was prepared using N-methyl-4-hydroxypiperidine
(without treatment with TFA). ESMS
(C.sub.30H.sub.44N.sub.2O.sub.2): calcd. 464.34; obsd. 465.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.996 min. .sup.1H-NMR (CD.sub.3OD, 299.96 MHz): .delta.
(ppm) 0.57 (t, 6H) 1.31 (d, 41), 1.36 (m, 3H), 1.84-2.65 (m,
10H),;2.99 (s, 6H), 3.20 (t, 1H), 3.40 (m, 4H), 3.67 (d, 1H), 4.78
(s, 1H), 6.98 (m, 4H), 7.18(m, 4H)
Example 112
[0355] Compound 112 was prepared using
N-methyl-3-hydroxymethylpiperidine (without treatment with TFA).
ESMS (C.sub.32H.sub.48N.sub.2O.sub.2): calcd. 492.37; obsd. 493.2
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.276 min. .sup.1H-NMR (CD.sub.3OD, 299.96 MHz): .delta.
(ppm) 0.47 (t, 6H), 1.18-1.57 (m, 6H), 1.76-2.16 (m, 6H), 2.36 (m,
2H), 2.56 (m, 2H), 2.94 (s, 6H), 2.99 (m, 4H), 3.36 (d, 2H), 3.72
(d, 2H), 3.94 (m, 2H), 4.08 (q, 2H), 6.94 (d, 4H), 7.16 (d, 4H)
Example 113
[0356] Compound 113 was prepared using
N-Boc-2-(2-hydroxyethyl)piperidine (without treatment with TFA).
ESMS (C.sub.32H.sub.48N.sub.2O.sub.2): calcd. 492.37; obsd. 493.5
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.492 min.
Example 114
[0357] Compound 114 was prepared prepared similarly as described in
Example 1, except replacing 4,4'-methylene-bis(2,6-dimethylphenol)
and the N-Boc-3-pyrrolidinol used with
4,4-methylene-bis(2,6-dimethylaniline) and
N-Boc-3-hydroxypyrrolidine, respectively. ESMS
(C.sub.25H.sub.36Cl.sub.2N.sub.4): calcd. 392.6; obsd. 393.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
4 min)=2.3 min.
Examples 115 to 124
[0358] Unless otherwise noted, compounds 115 to 124 were prepared
similarly as described in Example 1, except replacing
4,4'-methylene-bis(2,6-dimethylphenol) and the N-Boc-3-pyrrolidinol
used with 4,4'-methylene-bis(2chlorophenol) and the requisite
alcohol, respectively.
Example 115
[0359] Compound 115 was prepared using N-(2-hydroxyethyl)morpholine
(without treatment with TFA). ESMS
(C.sub.25H.sub.32Cl.sub.2N.sub.2O.sub.- 4): calcd. 494.17; obsd.
495.1 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=2.894 min.
Example 116
[0360] Compound 116 was prepared using
N,N-di-ethyl-5-amino-2-pentanol (without treatment with TFA). ESMS
(C.sub.31H.sub.48Cl.sub.2N.sub.2O.sub.- 2): calcd. 550.31; obsd.
551.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=3.357 min.
Example 117
[0361] Compound 117 was prepared using
N,N-di-methyl-3-amino-2,2-di-methyl- -propanol (without treatment
with TFA). ESMS (C.sub.27H.sub.40Cl.sub.2N.su- b.2O.sub.2): calcd.
494.25; obsd. 495.2 [M+H].sup.+. Retention time (anal. HPLC: 2-70%
MeCN/H.sub.2O over 4 min)=3.116 min.
Example 118
[0362] Compound 118 was prepared using N-methyl-4-hydroxypiperidine
(without treatment with TFA). ESMS
(C.sub.25H.sub.32Cl.sub.2N.sub.2O.sub.- 2): calcd. 462.18; obsd.
463.1 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=2.865 min.
Example 119
[0363] Compound 119 was prepared using
N,N-di-methyl-3-amino-2-propanol (without treatment with TFA). ESMS
(C.sub.23H.sub.32Cl.sub.2N.sub.2O.sub.- 2): calcd. 438.18; obsd.
439.1 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=2.832 min.
Example 120
[0364] Compound 120 was prepared using
N-methyl-2-(2-hydroxyethyl)piperidi- ne (without treatment with
TFA). ESMS (C.sub.29H.sub.40Cl.sub.2N.sub.2O.su- b.2): calcd.
518.25; obsd. 5519.2 [M+H].sup.+. Retention time (anal. HPLC: 2-70%
MeCN/H.sub.2O over 4 min)=3.304 min.
Example 121
[0365] Compound 121 was prepared using
N-methyl-2-(2-hydroxyethyl)pyrrolid- ine (without treatment with
TFA). ESMS (C.sub.27H.sub.36Cl.sub.2N.sub.2O.s- ub.2): 5 calcd.
490.22; obsd. 491.1 [M+H].sup.+. Retention time (anal. HPLC: 2-70%
MeCN/H.sub.2O over 4 min)=3.127 min.
Example 122
[0366] Compound 122 was prepared using
N-methyl-2-hydroxymethylpipenidine (without treatment with TFA).
ESMS (C.sub.27H.sub.36Cl.sub.2N.sub.2O.sub.- 2): calcd. 490.22;
obsd. 491.1 [M+H].sup.+. Retention time (anal. HPLC: 20-90%
MeCN/H.sub.2O over 4 min)=2.037 min.
Example 123
[0367] Compound 123 was prepared using N-methyl-3-pyrrolidinol
(without treatment with TFA). ESMS
(C.sub.23H.sub.28Cl.sub.2N.sub.2O.sub.2): calcd. 435.393; obsd.
436.0 [M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O
over 5 min)=2.49 min.
Example 124
[0368] Compound 124 was prepared using N-Boc-3-pyrrolidinol. ESMS
(C.sub.21H.sub.24Cl.sub.2N.sub.2O.sub.2): calcd. 407.3392; obsd.
408.0 [M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O
over 5 min)=2.51 min.
Examples 125 to 126
[0369] Unless otherwise noted, compounds 125 to 126 were prepared
similarly as described in Example 1, except replacing
4,4'-methylene-bis(2,6-dimethylphenol) and the N-Boc-3-pyrrolidinol
used with 4,4'-methylene-bis(2-methylphenol) and the requisite
alcohol.
Example 125
[0370] Compound 125 was prepared using N-methyl-3-pyrrolidinol
(without treatment with TFA). ESMS
(C.sub.25H.sub.34N.sub.2O.sub.2): calcd. 394.5572; obsd. 394.9
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min) 2.60 min.
Example 126
[0371] Compound 126 was prepared using N-Boc-3-pyrrolidinol. ESMS
(C.sub.23H.sub.30N.sub.2O.sub.2): calcd. 366.5035; obsd. 367.0
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.48 min.
Examples 127 to 134
[0372] Unless otherwise noted, compounds 127 to 134 were prepared
similarly as described in Example 1, except replacing
4,4'-methylene-bis(2,6-dimethylphenol) and the N-Doc-3-pyrrolidinol
used with 2,2'-methylene-bis(4-methylphenol) and the requisite
alcohol.
Example 127
[0373] Compound 127 was prepared using
N-methyl-3-hydroxypyrrolidine (without treatment with TFA). ESMS
(C.sub.25H.sub.34N.sub.2O.sub.2): calcd. 394.26; obsd. 395.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.733 min.
Example 128
[0374] Compound 128 was prepared using N-(2-hydroxyethyl)morpholine
(without treatment with TFA). ESMS
(C.sub.27H.sub.38N.sub.2O.sub.4): calcd. 454.28; obsd. 455.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.739 min.
Example 129
[0375] Compound 129 was prepared using
N,N-di-methyl-3-amino-2,2-di-methyl- -propanol (without treatment
with TFA). ESMS (C.sub.29H.sub.46N.sub.2O.sub- .2): calcd. 454.36;
obsd. 455.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70%
MeCN/H.sub.2O over 4 min)=3.097 min.
Example 130
[0376] Compound 130 was prepared using N-methyl-4-hydroxypiperidine
(without treatment with TFA). ESMS
(C.sub.27H.sub.38N.sub.2O.sub.2): calcd. 422.29; obsd. 423.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.867 min.
Example 131
[0377] Compound 131 was prepared using
N,N-di-methyl-3-amino-2-propanol (without treatment with TEFA).
ESMS (C.sub.25H.sub.38N.sub.2O.sub.2): calcd. 398.29; obsd. 399.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.813 min.
Example 132
[0378] Compound 132 was prepared using
N-methyl-2-(2-hydroxyethyl)piperidi- ne (without treatment with
TFA). ESMS (C.sub.31H.sub.46N.sub.2O.sub.2): calcd. 478.36; obsd.
479.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=3.164 min.
Example 133
[0379] Compound 133 was prepared using
N-methyl-2-(2-hydroxyethyl)pyrrolid- ine (without treatment with
TFA). ESMS (C.sub.29H.sub.42N.sub.2O.sub.2): calcd. 450.32; obsd.
451.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=3.011 min.
Example 134
[0380] Compound 134 was prepared using
N-methyl-2-hydroxymethylpiperidine (without treatment with TFA).
ESMS (C.sub.29H.sub.42N.sub.2O.sub.2): calcd. 450.32; obsd. 451.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=3.173 min.
Examples 135 to 143
[0381] Unless otherwise noted, compounds 135 to 143 were prepared
similarly as described in Example 1, except replacing
4,4'-methylene-bis(2,6dimethylphenol) and the N-Boc-3-pyrrolidinol
used with 2,2'-dihydroxy-diphenyl ether and the requisite
alcohol.
Example 135
[0382] Compound 135 was prepared using
N-methyl-3-hydroxypyrrolidine (without treatment with TFA). ESMS
(C.sub.22H.sub.28N.sub.2O.sub.3): calcd. 368.21; obsd. 369.1
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.302 min.
Example 136
[0383] Compound 136 was prepared using N-(2-hydroxyethyl)morpholine
(without treatment with TFA). ESMS
(C.sub.24H.sub.32N.sub.2O.sub.5): calcd. 428.23; obsd. 429.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.270 min.
Example 137
[0384] Compound 137 was prepared using
N,N-di-methyl-3-amino-2,2-di-methyl- -propanol (without treatment
with TFA). ESMS (C.sub.26H.sub.40N.sub.2O.sub- .3): calcd. 428.30;
obsd. 429.2 [M+H].sup.+. Retention time (anal. HPLC: 2-70%
MeCN/H.sub.2O over 4 min)=2.664 min.
Example 138
[0385] Compound 138 was prepared using N-methyl-4-hydroxypiperidine
(without treatment with TFA). ESMS
(C.sub.24H.sub.32N.sub.2O.sub.3): calcd. 396.24; obsd. 397.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.460 min.
Example 139
[0386] Compound 139 was prepared using
N-methyl-3-hydroxymethylpiperidine (without treatment with TFA).
ESMS (C.sub.26H.sub.36N.sub.2O.sub.3): calcd. 424.27; obsd. 425.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.785 min.
Example 140
[0387] Compound 140 was prepared using
N,N-di-methyl-3-amino-2-propanol (without treatment with TFA). ESMS
(C.sub.22H.sub.32N.sub.2O.sub.3): calcd. 372.24; obsd. 373.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.483 min.
Example 141
[0388] Compound 141 was prepared using
N-methyl-2-(2-hydroxyethyl)piperidi- ne (without treatment with
TFA). ESMS (C.sub.28H.sub.40N.sub.2O.sub.3): calcd. 452.30; obsd.
453.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=2.836 min.
Example 142
[0389] Compound 142 was prepared using
N-methyl-2-(2-hydroxyethyl)pyrrolid- ine (without treatment with
TFA). ESMS (C.sub.26H.sub.36N.sub.2O.sub.3): calcd. 424.27; obsd.
425.2 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=2.573 min.
Example 143
[0390] Compound 143 was prepared using
N-methyl-2-hydroxymethylpiperidine (without treatment with TFA).
ESMS (C.sub.26H.sub.36N.sub.2O.sub.3): calcd. 424.27; obsd. 425.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.711 min.
Examples 144 to 151
[0391] Unless otherwise noted, compounds 144 to 151 were prepared
similarly as described in Example 1, except replacing
4,4'-methylene-bis(2,6-dimethylphenol) and the N-Boc-3-pyrrolidinol
used with 4,4'-dihydroxy-diphenyl ether and the requisite
alcohol.
Example 144
[0392] Compound 144 was prepared using
N-methyl-3-hydroxypyrrolidine (without treatment with TFA). ESMS
(C.sub.22H.sub.28N.sub.2O.sub.3): calcd. 368.21; obsd. 369.1
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.333 min.
Example 145
[0393] Compound 145 was prepared using N-(2-hydroxyethyl)morpholine
(without treatment with TFA). ESMS
(C.sub.24H.sub.32N.sub.2O.sub.5): calcd. 428.23; obsd. 429.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.291 min.
Example 146
[0394] Compound 146 was prepared using
N,N-di-methyl-3-amino-2,2-di-methyl- -propanol (without treatment
with TFA). ESMS (C.sub.26H.sub.40N.sub.2O.sub- .3): calcd. 428.30;
obsd. 429.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70%
MeCN/H.sub.2O over 4 min)=2.826 min.
Example 147
[0395] Compound 147 was prepared using N-methyl-4-hydroxypiperidine
(without treatment with TFA). ESMS
(C.sub.24H.sub.32N.sub.2O.sub.3): calcd. 396.24; obsd. 397.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.513 min.
Example 148
[0396] Compound 148 was prepared using
N-methyl-3-hydroxymethylpiperidine (without treatment with TFA).
ESMS (C.sub.26H.sub.36N.sub.2O.sub.3): calcd. 424.27; obsd. 425.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.905 min.
Example 149
[0397] Compound 149 was prepared using
N-methyl-2-(2-hydroxyethyl)piperidi- ne (without treatment with
TFA). ESMS (C.sub.28H.sub.40N.sub.2O.sub.3): calcd. 452.30; obsd.
453.3 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=2.821 min.
Example 150
[0398] Compound 150 was prepared using
N-methyl-2-(2-hydroxyethyl)pyrrolid- ine (without treatment with
TFA). ESMS (C.sub.26H.sub.36N.sub.2O.sub.3): calcd. 424.27; obsd.
425.2 [M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O
over 4 min)=2.780 min.
Example 151
[0399] Compound 151 was prepared using
N-methyl-2-hydroxymethylpiperidine (without treatment with TFA).
ESMS (C.sub.26H.sub.36N.sub.2O.sub.3): calcd. 424.27; obsd. 425.2
[M+H].sup.+. Retention time (anal. HPLC: 2-70% MeCN/H.sub.2O over 4
min)=2.749 min.
Examples 152 to 154
[0400] Unless otherwise noted, compounds 152 to 154 were prepared
similarly as described in Example 1, except replacing
4,4'-methylene-bis(2,6-dimethylphenol) and the N-Boc-3-pyrrolidinol
used with 2,2'-methylene-bis(6-methylphenol), and the requisite
alcohol, respectively.
Example 152
[0401] Compound 152 was prepared using
N-methyl-4-hydroxy-piperidine (without treatment with TFA). ESMS
(C.sub.27H.sub.38N.sub.2O.sub.2): calcd. 422.61 1; obsd. 423.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.60 min.
Example 153
[0402] Compound 153 was prepared using N-methyl-3-pyrrolidinol
(without treatment with TFA). ESMS
(C.sub.25H.sub.34N.sub.2O.sub.2): calcd. 394.5572; obsd. 395.1
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=2.71 min.
Example 154
[0403] Compound 154 was prepared using N-methyl-2-piperidineethanol
(without treatment with TFA). ESMS
(C.sub.31H.sub.46N.sub.2O.sub.2): calcd. 478.7185; obsd. 479.3
[M+H].sup.+. Retention time (anal. HPLC: 10-70% MeCN/H.sub.2O over
5 min)=3.21 min.
Example 155
Determination of Sodium Channel Activity
[0404] Measurement of Sodium Channel Activity in Neonatal Rat
Cerebellar Granule Neurons.
[0405] (a) Primary culture of rat cerebellar granule neurons:
[0406] Primary cultures of cerebellar granule neurons were prepared
as described previously (Gallo et al., 1990; J. Neurochem: 54,
1619-25). Briefly, cerebella were dissected from 7 to 8 day-old
Sprague-Dawley rats and cut into pieces using a McIIwain tissue
chopper. Tissue pieces were incubated with 0.025% trypsin in Hanks
Balanced Salt Solution (HBSS) for 10 min at 37.degree. C. Following
enzyme treatment, the tissue pieces were resuspended in HBSS buffer
containing 2.8 mg/ml soybean trypsin inhibitor and 0.006% DNase and
dissociated mechanically by trituration with a fire-polished glass
pipette. The cell suspension then was centrifuged at 1000 g for 5
min, the supernatant discarded and the pellet resuspended in
DMEM/F12 supplemented with 10% fetal bovine serum, 30 mM glucose,
25 mM KCl, 1 mM glutamine, 1 mM sodium pyruvate, N2 supplement and
penicillin (20 U/ml)-streptomycin (20 mg/ml)-amphotericin B. Cells
were plated in 96-well poly-D-lysine-coated black wall-clear bottom
culture plates at a concentration of 1-2.times.10.sup.5 cells/well.
Cells were maintained at 37.degree. C. in an atmosphere containing
5% CO.sub.2. After 18-24 h, cytosine arabinoside (10 mM final
concentration) was added, to inhibit replication of non-neuronal
cells. All experiments were performed using cultures maintained for
4-6 days in vitro (4-6 DIC).
[0407] 2. Analysis of sodium channel activity in rat cerebellar
granule neurons using the fluorescent imaging plate reader
(FLIPR):
[0408] To measure sodium channel activity, veratridine-evoked
increases in intracellular Ca.sup.2+([Ca.sup.2+].sub.i) in
fluo-4/AM loaded cerebellar granule neurons were monitored, in
real-time, using the FLIPR (Molecular Devices, Sunnyvale, Calif.).
Cerebellar granule neurons, at 4-6 DIC, were incubated with 4 mM
fluo-4/AM in HBSS buffer containing 2.5 mM probenecid and 0.04%
pluronic acid for 45 min at 37.degree. C. The neurons then were
washed three times with HBSS containing 2.5 mM probenecid (FLIPR
buffer). The plates were transferred to the FLIPR and the cells
incubated for 5 min in FLIPR buffer, in the absence (control) or
presence of antagonist, prior to addition of veratridine (40
.mu.M). Cell fluorescence (.lambda..sub.Ex=488 nm;
1.sub.Em.gtoreq.510 nm) was monitored both before and after the
addition of veratridine. Peak fluorescence intensity, after
veratridine addition, was determined using the FLIPR software.
Curve fitting and parameter estimation (pIC.sub.50) were performed
using GraphPad. Stock solutions (10 mM) of compounds were made in
100% DMSO.
[0409] Compounds of the invention corresponding to Examples 27,
29-33, 35-39, 41, 42, 44, 46, 48, 50-59, 61, 62, 64-70, 72-74,
76-83, 86-94, 96, 97, 101-110, 112, 115-134, 137, 139, 141, 143,
146, 148-150, and 152-154have an IC.sub.50value of less than 100
.mu.M in this assay. Compounds of Examples 45, 47, 60, 84, 85, 100,
111, 135, 136, 138, 140, 142, 144, 145, 147, and 151 exhibited less
than 50% inhibition of the control response at 100 .mu.M, the
highest concentration tested. No IC.sub.50 value was obtained for
these compounds although they are expected to demonstrate sodium
channel activity at higher concentrations. Compounds of Examples
28, 34, 40, 43, 49, 63, 71, 75, 95, 98, 99, 113, and 114 were not
tested. In general, compounds of the invention corresponding to
Examples 1-26 have an IC.sub.50 value of less than 100 .mu.M in a
rat cerebellar granule neuron assay.
Example 156
In Vivo Pain Model
[0410] The ability of an agent or a combination of agents to treat
pain can be determined using known pharmacological models (for
example see Kim, S. H. and Chung, J. M., Pain, 1992, 50, 355-363),
or using models that are similar to known models.
[0411] Male Sprague-Dawley rats (120-180 g, Harlan, Indianapolis,
Ind.) are pre-screened to determine their baseline 50% withdrawal
threshold using a set of von Frey filaments. The 50% withdrawal
threshold for mechanical stimulation to the hind paw is determined
by the up-down method described by Dixon W. J., Ann. Rev.
Pharmacol. Toxicol., 1980, 20, 441-462.
[0412] Briefly, 8 von Frey filaments with approximately equal
logarithmic incremental (0.22) bending forces are chosen (von Frey
numbers: 3.65, 3.87, 4.10, 4.31, 4.52, 4.74, 4.92, and 5.16;
equivalent to: 0.45, 0.74, 1.26, 2.04, 3.31, 5.50, 8.32, and 14.45
g). A von Frey filament is applied perpendicularly to the plantar
surface with sufficient force to bend it slightly and held for 3-5
seconds. An abrupt withdrawal of the foot during stimulation or
immediately after the removal of stimulus is considered a positive
response.
[0413] Whenever there is a positive or negative response, the next
weaker or stronger filament is applied, respectively. The test is
continued until six stimuli after the first change in response has
been obtained. The pattern of positive and negative responses is
converted into a 50% threshold value using the following formula:
50% threshold=10.sup.{circum- flex over ( )}(X+kd)
10.sup.{circumflex over ( )}4, where X=the value of the final von
Frey filament used (in log units), k=the tabular value for the
pattern of positive/negative responses [obtained from Dixon], and
d=the mean difference between stimuli in log units (0.22). In the
cases where continuous positive or negative responses are observed
all the way out to the end of the stimulus spectrum, values of 0.3
g or 15.0 g are assigned, respectively. For ED.sub.50 calculations,
a linear regression is determined for responses one either side of
the 50% reversal and then an approximation is determined based upon
the value which intersects the 50% point.
[0414] After pre-screening, rats which display a 50% withdrawal
threshold greater than 8 g are acceptable for surgery. The spinal
nerve ligation (SNL) surgery is carried out as follows. Rats are
anesthetized with inhaled Isoflurance and the left L5 and L6 spinal
nerves are tightly ligated with 6-0 silk thread. Postoperatively,
rats are placed under a heat lamp until motor function returns and
then single-housed. At 5-7 days post surgery, rats are re-tested to
determine their post-surgery 50% withdrawal threshold. Rats which
consistently display (2 or more days) a 50% withdrawal threshold
less than 4.5 g are considered acceptable for compound
investigation.
[0415] Experimental studies typically involve one or more
therapeutic compounds, a standard (control), and a vehicle group.
Compounds are formulated in saline for injection and pH adjusted
with dilute sodium hydroxide. Groups sizes are normally 5 or 6
rats. For routine screening of compounds, a single dose is used
(normally 30 mg/kg) and the compound is administered
intraperitoneally (typically 2-4 ml/kg). At 1, 3, and 6 hours post
administration, the 50% withdrawal threshold is determined by an
investigator who is blinded to the treatment groups. If at 6 hours,
some prolonged activity is present, i.e., 50% withdrawal thresholds
greater than 8 g, then later timepoints may be attempted (normally
at 12 and 24 hours). Compounds can also be administered orally to
determine oral activity.
[0416] Compounds which show moderate activity in the screening
studies are re-tested over a range of doses in order to construct a
dose response curve and generate an ED.sub.50. The ED.sub.50 values
are used to compare compound potencies. The compounds of this
invention tested in this model were effective for treating
pain.
[0417] While the present invention has been described with
reference to the specific embodiments thereof, it should be
understood by those skilled in the art that various changes may be
made and equivalents may be substituted without departing from the
true spirit and scope of the invention. In addition, many
modifications may be made to adapt a particular situation,
material, composition of matter, process, process step or steps, to
the objective, spirit and scope of the present invention. All such
modifications are intended to be within the scope of the claims
appended hereto. Additionally, all publications, patents, and
patent documents cited hereinabove are incorporated by reference
herein in full, as though individually incorporated by
reference.
* * * * *